Proteinuria and Microalbuminuria in Adults; Significance, Evaluation

ICME Topic

Proteinuria and Microalbuminuria in Adults;Significance, Evaluation, and TreatmentK.K. Venkat, MD

Abstract: This paper reviews current concepts regarding the patho-physiology, diagnostic evaluation, and treatment of microalbuminuriaand proteinuria in adults. Microalbuminuria (in diabetics) and protein-uria are early markers for potentially serious renal disease, and areassociated with increased risk of atherosclerotic cardiovascular disease.Proteinuria also contributes to renal scarring, and accelerates the pro-gression of chronic kidney disease to end-stage renal failure. Screeningof diabetics for microalbuminuria, and the initial workup of proteinuria,should occur in the primary care setting. Reduction of microalbumin-uria in diabetics may retard its progression to overt diabetic nephropa-thy. Therapy of renal diseases should aim for optimal blood pressurecontrol and the maximum possible reduction in urinary protein excre-tion. Angiotensin-converting en2yme inhibitor (ACE-I) and/or angio-tensin-receptor blocker (ARB) therapy is the most effective measure toachieve this. These drugs also provide protection against the cardiovas-cular problems that are highly prevalent in this patient population.

Key Words: angiotensin-converting enzyme inhibitors, angioten-sin-receptor blockers, chronic kidney disease, microalbuminuria,proteinuria

Proteinuria is a well-known marker for renal disease.' Theassociation of heavy proteinuria (nephrotic syndrome) with

edema, hypoalbuminemia, hyperlipidemia, hypercoagulability/thromboembolism, and susceptibility to infection is also wellrecognized.^ Over the past two decades, evidence for a directadverse impact by proteinuria on the progression of chronickidney disease to end-stage renal failure has accumulated.̂ "'*Proteinuria and microalbuminuria are also associated with in-creased risk of atherosclerotic cardiovascular disease. '̂* Thereare approximately 19 million Americans with chronic kidneydisease,^ and the vast majority of them will have proteinuria asa manifestation of renal disease. Thus, proteinuria is commonlyencountered in the primary care setting.

From the Division of Nephrology, Department of Medicine, Henry FordHospital, Detroit, Ml.

Reprint requests to K.K. Venkat, MD, Senior Staff Physician, Division ofNephrology, Department of Medieine, Henry Ford Hospital, 2799 WestGrand Blvd., Detroit, Ml 48202. Email: [email protected]

Aceepted June 15, 2004.

Copyright © 2004 by The Southem Medical Association

0038-4348/04/9710-0969

DefinitionsNormal adults excrete less than 150 to 200 mg/d of pro-

tein in the urine.'^~"' Very little of this protein is albumin (lessthan 10—20 mg/d). Albumin excretion in the range of 30 to300 mg/d or, as is more commonly repotted, 30 to 300 mg/gof urinary creatinine, is referred to as microalbuminuria. Atthese levels, standard dipsticks do not detect albumin in theurine, and specific measurement of albumin using highly al-bumin-sensitive techniques is required. Although gender-spe-cific limits for normal urinary albumin excretion have beensuggested (17 mg/g of creatinine for men and 25 mg/g inwomen),'' for clinical purposes, using the same cut-off valuefor both sexes is sufficient.

Key Points• Persistent microalbuminuria (in diabetics) and overt

proteinuria are important markers for the subsequentdevelopment of progressive chronic kidney disease,and are also associated with a high risk of cardiovas-cular disease.

• The total daily urinary excretion of albumin or proteinis reliably quantitated by the ratio of their concentra-tion to the concentration of creatinine in a randomurine sample. Testing a random sample of urine haslargely replaced the cumbersome 24-hour urine col-lection in clinical practice.

• Reduction of microalbuminuria in diabetics and overtproteinuria irrespective of etiology, together with strictblood pressure control, is helpful in ameliorating theprogression of chronic kidney disease.

• Identifying and correcting cardiovascular risk factorsare key aspects of managing microalbuminuric andovertly proteinuric patients.

• The use of an angiotensin-converting enzyme inhibi-tor (ACE-1) and/or an angiotensin-reeeptor blocker(ARB) is the most effective way of ameliorating theseurinary abnormalities.

• Screening for microalbuminuria and overt proteinuria,and timely referral for nephrology evaluation of thesepatients in the primary care setting, is criticallyimportant.

Southern Medical Journal • Volume 97, Number 10, October 2004 969

Venkat • Proteinuria and Microalbuminuria in Adults

The terms "proteinuria" and "albuminuria" are often usedsynonymously in the medical literature. This is generally ac-ceptable, since in general the most abundant urinary proteinin patients with renal disease is albumin. However, it shouldbe remembered that the standard dipstick is almost exclu-sively sensitive to albumin. Strictly speaking, a positive dip-stick test should therefore be referred to as albuminuria (ormacroalbuminuria, to differentiate it from microalbuminuria)rather than proteinuria, since other proteins in the urine, suchas globulins, light chains, and glycoproteins are not detectedby dipstick testing. Besides macroalbuminuria, other termsused to refer to standard dipstick-positive proteinuria are"overt" proteinuria and "clinical" proteinuria. In the rest ofthis article, the term overt proteinuria will be used to refer toa positive standard dipstick test. National Health and Nutri-tional Examination Survey III data reveal a prevalence ofmicroalbuminuria of 10.6% and overt proteinuria of 1.1% inthe US adult population.^

Renal Barriers to Protein Excretion, andMechanisms of Abnormal Proteinurla

In the normal kidney, the negatively charged glomerularcapillary wall repels negatively charged albumin and preventsits filtration (charge-barrier).' The slit-pores between thepodocytes in the glomerular capillary wall are small enough

to exclude larger proteins such as globulins from the glomer-ular filtrate (size-barrier). The role of structural proteins, suchas nephrin, podocin, and a-actinin, normally present in theslit-pores in preventing protein filtration has recently come tobe recognized.'^ Inherited abnormalities in these proteins re-sult in hereditary forms of nephrotic syndrome.

Glomerular charge and size barriers allow the passageinto the glomerular filtrate of only small, positively chargedproteins such as ji-2 microglobulin and immunoglobulin lightchains, and small amounts of albumin. The proximal tubularepithelium reabsorbs and catabolizes most of the proteins thatescape the glomerular barriers.^ Glomerular filtration of pro-tein, therefore, contributes minimally to normal urine proteincontent. Most of the protein in normal urine is the Tamm-Horsfall glycoprotein secreted by the renal tubules.**"'" Table1 shows the pathophysiologic mechanisms that underlie in-creased urinary protein excretion in various disorders.

Qualitative Tests for Urinary ProteinDipsticks or tablets that can detect microalbuminuria are

available for qualitative screening of the urine (Micral dipstick[Boehringer Mannheim Diagnostics, Indianapolis, IN], Micro-bumintest tablet [Ames Miles Laboratories, Elkhart, IN]). How-ever, the definitive diagnosis of microalbuminuria requires quan-

Table 1. Pathophysiologic mechanisms in proteinuria

Mechanism Causes

"Overflow" proteinuria

High blood levels of positively charged small molecular weight light chainsescape glomerular charge and size barriers and overwhelm tubular capacityto reabsorb and catabolize them.'''"

Glomerular proteinuria

Selective—loss of only the glomerular charge-barrier, albumin excretedpredominantly.^

Non-seleetive—loss of both the charge and size-barrier with excretion ofalbumin and larger molecular weight proteins (such as IgG).^

Tubular proteinuria

Albumin and larger proteins restricted by intact glomerular barriers. Smallmolecular weight proteins normally freely filtered at the glomerulus (suchas j3-2 microglobulin) escape reabsorption/catabolism because of renaltubular damage.'''"

Posturai proteinuria

Abnormal protein excretion in the upright posture, with normal urinaryprotein excretion in recumbency, probably due to exaggerated systemic andglomerular hemodynamic responses in the upright posture.'''"'"'

"Admixture" proteinuria

Gross hematuria with tests for urinary protein detecting protein present inblood mixed with urine. No renal pathology.

"Physiologic"/transient proteinuria

Probably due to transient glomerular hemodynamic changes.

Multiple myeloma; other paraproteinemic states.

Minimal change disease.

Glomerulopathies other than minimal change disease.

Early stages of various tubulointerstitial disorders. "Secondary"glomerular pathologic changes developing in the later stages maycause glomerular proteinuria in patients with tubulointerstitialdisorders.

Otherwise normal subjects with structurally normal kidneys.Oecasionally might mark beginning of more serious renal disease.

Urological causes of hematuria such as calculi and cancer. Dailyprotein excretion usually <1 g. If the random urine protein tocreatinine ratio is > 1.0 underlying glomerular disease is the likelycause of gross hematuria.

Exercise, fever, congestive heart failure.

970 © 2004 Southern Medical Association

CME Topic

titation of albumin excretion by enzyme-linked immunoassay(ELISA)/radloimmunoassay/nephelometry techniques.^

As stated above, standard dipsticks detect predominantlyalbumin, and are not sensitive to other proteins such as glob-ulins, glycoproteins, and immunoglobulin light chains.* Theless commonly used sulfosalicylic acid test (Bumintest) de-tects albumin and other proteins in the urine. Thus, a stronglypositive sulfosalicylic acid test, with a weak or negative dip-stick test, implies the presence of proteins other than albumin(such as immunoglobulin light chains), and suggests the di-agnosis of disorders such as multiple myeloma.^ False posi-tive results may occur with both dipstick and sulfosalicylicacid tests, but are rare.^ Qualitative testing of urine needs tobe repeated to confirm persistence of overt proteinuria beforea work-up is undertaken.

Quantitation of Microalbuminuria andOvert Proteinuria

In patients with a negative standard dipstick test, themagnitude of microalbuminuria can be determined by mea-suring the concentration of albumin in either a random("spot") sample or a timed collection (usually 24 hours) ofurine. Random sampling of the urine is the preferred method,because it avoids the need for the cumbersome 24-hour urinecollection. The most commonly used method of expressingthe result of the microalbuminuria test is milligrams of albu-min/gram of creatinine in the random sample of urine. Iftimed urine collection is used, the results are expressed asmilligrams of albumin/24 hours or micrograms of albumin/min. Normal values for albumin excretion and levels thatdefine microalbuminuria have been discussed earlier.

The quantity of overt proteinuria revealed by dipsticktesting is affected by the concentration of the urine sam-ple.^''° Dilute urine might result in a weakly positive test,despite the presence of large amounts of protein, and thereverse occurs in highly concentrated urine. Twenty-four hoururine collection, the time-honored method for quantitation ofovert proteinuria, is cumbersome and often inaccurate due tocollection errors. When renal function (whether normal orimpaired) is stable, the ratio of the concentration of urineprotein (mg/dL) to urine creatinine (mg/dL) (urine protein/urine creatinine ratio) in a random sample correlates wellwith the 24-hour urinary protein excretion, because the dailyexcretion of creatinine in the urine is fixed.'•'•''' Creatinine isa product of skeletal muscle metabolism. Daily generation ofcreatinine depends on the muscle mass of the individual, and,therefore, varies with age and gender. Adults with averagemuscle mass excrete approximately 1,000 mg/d of urinarycreatinine. Thus, a random urine protein/urine creatinine ratioof <0.2 indicates a normal 24-hour urinary protein excretionof less than <0.2 g, a ratio between 0.2 and 3.5 indicates a

daily excretion of greater than 0.2 g but less than 3.5 g, andvalues greater than 3.5 indicate a daily protein excretion ofmore than 3.5 g.'"-'^

There may be significant day-to-day variations of up to15 to 40% in daily total urinary protein excretion both innormal subjects and those with renal disease. This is due tothe effects on urinary protein excretion of variables such asphysical activity, dietary salt and fluid intake, and blood pres-sure. There is also diurnal variation in urinary protein excre-tion (highest between 6 AM and noon). Hence the recommen-dation to check the second voided morning specimen tomeasure the microalbumin or protein to creatinine ratio. How-ever, for the purposes of clinical practice, the time of the dayat which the random urine sample is obtained is generally notimportant.

It should be noted that in subjects with above- or below-average muscle mass, the random urine protein/tirine creatinineratio may not correspond numerically to the total 24-hour ex-cretion of protein. For example, in a person with less than av-erage muscle mass excreting only 600 mg/d of urinary creati-nine, a random urine protein/urine creatinine ratio of 3.0represents daily protein excretion of 1.8 g, whereas in a verymuscular individual excreting 1,500 mg/d of creatinine, thesame ratio of 3.0 will indicate daily protein excretion of 4.5 g.The main value of the easily measured random urine protein/urine creatinine ratio is to classify patients based on the magni-tude of proteinuria, and consider in the differential diagnosisrenal disorders characterized by these different levels of urinaryprotein excretion. The ratio is also an easy way of following thetrend in proteinuria over time in individual patients.

"Benign" Postural ProteinuriaElevated urinary protein excretion in samples obtained in

the upright posture (day or ambulatory samples) with normalprotein excretion in samples obtained in recumbency (nightsamples) is referred to as postural proteinuria.'^ The randomurine protein/urine creatinine ratio in a sample obtained in theupright posture can not be compared with that obtained afterovernight recumbency to make the diagnosis of this conditionbecause of diurnal variations in the glomerular filtration rateresulting in moment-to-moment variations in the excretion ofurinary protein and creatinine.'° Separate collection of thetotal volume of urine excreted during the day and night isrequired to identify postural proteinuria. Almost exclusivelyseen in patients less than 30 years of age (because posturalproteinuria frequently disappears in older patients), this con-dition is characterized by normal renal function, blood pres-sure, and urinary sediment, and daily urinary protein excre-tion usually of less than a gram (random urine protein/urinecreatinine ratio <1.0).'^ Most of these patients do not de-velop progressive renal disease on prolonged observation,and hence the epithet "benign." Occasionally, postural pro-teinuria may be the initial presentation of more serious renal



disease. Periodic monitoring of the renal status of patientswith postural proteinuria is, therefore, warranted.

Subnephrotic Proteinuria and NephroticSyndrome

Patients with subnephrotic proteinuria (>0.2 g and<3.5 g/d, or random urine protein/urine creatinine ratio of>0.2 and <3.5) may have either nonglomerular renal disease(tubulointerstitial, vascular, or cystic disorders) or a glomeru-lopathy.'" Early or mild glomerular damage, severe reductionin the glomerular filtration rate or marked reduction in serumprotein level can result in subnephrotic proteinuria in patientswith glomerulopathies. Even patients with initially subne-phrotic proteinuria may eventually progress to end-stage re-nal disease. Thus the magnitude of proteinuria alone cannotbe used to assess the severity of kidney disease.

Nephrotic syndrome is defined as proteinuria of >3.5 g/d(random urine protein/urine creatinine ratio >3.5) and is onlycaused by glomerular disease.^-'" Other features of the ne-phrotic syndrome, such as edema, hypoalbuminemia, hyper-lipidemia, thromboembolism, and increased susceptibility toinfection, are not always present. Classification of overt pro-teinuria on the basis of the quantity and type of protein, andthe causes of different levels of proteinuria, are shown inTable 2.

Contribution of Proteinuria to ProgressiveRenal Damage

The loss of a critical number of nephrons, irrespective ofthe initial cause, results in self-perpetuating and progressiverenal scarring. Elevated glomerular filtration rate, sustainedby increased intraglomerular pressure and glomerular hyper-

trophy (both mediated by angiotensin II) in the initially un-damaged nephrons, are implicated in the inexorably progres-sive renal damage.̂ '"'•"•̂ *' Hyperfiltration in intact remnantglomeruli can compensate for the loss of function in the initiallydamaged nephrons, but is eventually maladaptive. Elevated in-traglomerular pressure and glomerular hypertrophy lead to pro-gressive glomerulosclerosis, thus accelerating the loss of renalfunction. Other factors contributing to the self-perpetuating lossof renal function include systemic hypertension, high dietaryprotein intake, anemia, hyperlipidemia, elevated calcium-phosphate product resulting fi'om renal failure, intercurrent renalinsults (eg, the use of nephrotoxic drugs [nonsteroidal antiin-flammatory drugs, iodinated radiologic contrast, aminoglyco-sides], pyelonephritis, obstructive uropathy), and cigarette

Over the past two decades proteinuria itself has beenimplicated as a cause of progressive renal damage."'''' Severallarge human trials have shown that the greater the magnitudeof baseline proteinuria, the faster the progression of renalfailure. Furthermore, the decrease in proteinuria during ther-apy in these trials correlated strongly with slower progressionof chronic kidney disease, independent of the degree of bloodpressure control.̂ ^" '̂* These observations suggest a patho-genic role for proteinuria in progressive renal injury. Therapyis generally more effective in slowing the progression ofchronic renal failure in patients with heavy baseline protein-uria. However, a beneficial effect has also been shown inpatients with lesser levels of proteinuria.''^

In experimental studies, increased protein filtration acrossthe glomerular capillary wall and tubular reabsorption/catabolism of larger than normal amount of filtered protein havebeen shown to induce the production of pro-inflammatory and

Table 2. Classification of proteinuria based on quantity of protein excreted

Quantity of urinary protein Causes

Normoalbuminuria/normal urinary proteinLess than 200 mg/d of total protein with less than 10-20 mg of albumin/d

(random urine protein/urine creatinine ratio <0.2).

Microalbuminuria

Albumin excretion of 30-300 mg/day or 30-300 mg/g of urinary creatinineor >20 meg/minute. At these levels, dipstiek testing does not detectalbuminuria. Measuring the albumin/creatinine ratio (mg/g) in a randotn/"spot," urine sample is the preferred method.

Overt proteinuria—subnephrotic range

Albumin excretion of >300 mg/d or >300 mg/g of urinary creatinine or>200 meg/minute. Total daily protein excretion >300 mg and <3.5 g(random urine protein/urine creatinine ratio >0.2-<3.5). Dipstickpositive for albuminuria.

Nephrotic range proteinuria

Excretion of >3.5 g/d of protein (random urine protein/urine creatinineratio >3.5)

Normal individuals.

Early, "subclinical" diabetic nephropathy. Not enough studies todetermine the value of microalbuminuria screening in the earlystages of other glomerular diseases, hypertensives and metabolicsyndrome patients.

Tubulointerstitial, vascular and cystic diseases of the kidney.Glomerular diseases in their early/milder stage or in the settingof marked reduction in glomerular filtration rate or serumprotein levels. Proteinuria of >2 g/d (random urine protein/urine ereatinine ratio >2.0) is rare in tubulointerstitial/vascular/cystic diseases and is very suggestive of glomerular disease.

Various glomerular diseases.


CME Topic

fibrogenic cytokines, and increase the expression of adhesionmolecules and chemoattractants.^''"^^ The induction of thesemolecules by proteinuria contributes to progressive giomerulo-sclerosis, tubular atrophy, interstitial fibrosis, and vascular scle-rosis, and thus accelerates the loss of renal function. Reductionin urinary protein excretion is now recognized as an importanttherapeutic goal in chronic kidney disease.'^~"'^'

Importance of the Early Detection and Evaluationof Microalbuminuria and Overt Proteinuria

Even if the glomerular filtration rate is normal, detectionof microalbuminuria is important for two reasons. It is anearly marker for the subsequent development of nephropathyin diabetics.'*"''*' Strict glycemic"^ and blood pressure control,especially with an angiotensin-converting enzyme inhibitor(ACE-I) or angiotensin-receptor blocker (ARB) may mini-mize the risk of progression of microalbuminuria to overtproteinuria and clinical diabetic nephropathy."* "̂"*^ However,the value of microalbuminuria as a predictor of the subse-quent development of overt diabetic nephropathy has beenquestioned. A recent study showed a 58% incidence of re-gression of microalbuminuria unrelated to ACE-I use.'*^ It hasbeen suggested that screening for microalbuminuria may bevaluable in hypertensives and in patients with the metabolicsyndrome (syndrome X),'* '̂*^ but this has not yet become anestablished clinical practice guideline.

End-stage renal disease has become a major worldwidepublic health problem. In the United States, over 350,000patients are currently sustained by dialysis or renal transplan-tation, at a cost of over $15 billion to the taxpayer."*^ Theincidence and prevalence of end-stage renal disease is ex-pected to double over the next decade due to the increasinglife-expectancy of the population, and the increased incidenceof predisposing diseases, such as type-2 diabetes and hyper-tension.^"'^' The National Kidney Foundation has classifiedchronic kidney disease into 5 stages (Table 3)." Overt pro-teinuria is usually the initial manifestation of chronic kidneydisease. As already discussed, reducing urinary protein ex-cretion may help to slow the progression of chronic kidneydisease of any etiology'*~'^'^' and help to delay the need forrenal replacement therapy (dialysis or transplantation). Theimportance of timely screening for and evaluation of mi-croalbuminuria and overt proteinuria in the primary care set-ting, followed, if indicated, by early nephrology referral can-not be overemphasized.

Microalbuminuria is also a marker for generalized endo-thelial dysfunction and predicts increased risk of atheroscle-rotic cardiovascular disease.^'^ This risk increases markedlyand progressively with increasing overt proteinuria and de-creasing glomerular filtration rate.^^ Diligent search for andaggressive correction of all cardiovascular risk factors is war-ranted in this patient ^*^^^'

Table 3. Stages of chronic kidney disease"

Stage

Glomerutarfiltration rate

(mL/min/1.73 m Comments

>90

60-89

30-59

15-29

Normal renal function butmarkers for kidney diseasepresent: abnormal urinalysis,microalbuminuria, overtproteinuria, diabetes mellitus,hypertension or abnormalrenal imaging studies. Instituterenoprotective andeardioprotective measures.

Mild renal dysfunction. Instituteor continue renoprotective andeardioprotective measures.

Moderate renal dysfunction.Institute or continuerenoprotective andeardioprotective measures.

Advanced renal failure. Preparefor dialysis or transplantation.Institute or continueeardioprotective measures.

End-stage renal disease. Initiatedialysis or perform transplant.Institute or eontinueeardioprotective measures.

"Proposed by the National Kidney Foundation."

Diagnostic Evaluation ofMicroalbuminuria and Overt ProteinuriaMicroalbuminuria

Annual screening for microalbuminuria (if standard dip-stick testing is negative) starting 5 years after the diagnosis oftype 1, and at the time of diagnosis of type 2 diabetes mellitus(because it is difficult to time its onset) is recommended. '̂*'̂ ^Albumin excretion can vary on a day-to-day basis dependingon factors such as vigorous physical activity. Thus, persis-tence of microalbuminuria needs to be confirmed by retestingwithin 1 to 3 months before interventions to correct it areundertaken.

Overt proteinuriaIn healthy adults, periodic urinalysis to detect overt pro-

teinuria is not recommended as a health-maintenance mea-sure.^^ However, in the presence of risk factors for kidneydisease, such as diabetes mellitus and severe hypertension,annual testing by dipstick for overt proteinuria is impor-tant.''" A positive dipstick test indicates the presence ofalbumin in the urine, because it detects albumin almost ex-clusively, and obviates the need for ordering tests for mi-croalbuminuria. In overtly proteinuric patients, monitoringthe excretion of total proteins in the urine rather than albuminspecifically is preferable.^' Measuring albumin specifically is



Table 4. Laboratory studies in the evaluation of proteinuria: tests for assessing severity of the eausative renaldisease

Type of test Value of the test

Urinalysis including microscopy

Even in patients with normal renal function, urinalysis should be performedperiodically if risk factors for kidney disease (hypertension, diabetesmellitus and other indicators of stage I kidney disease) are present."

Detection of proteinuria. Proteinuria with microscopichematuria ("active" urinary sediment) generally suggestsmore severe glomerular damage.

Tests for microalbuminuria

Not required if dipstick is positive for albumin. For initial screening,albumin-sensitive dipstick or tablet can be used (Micral, Microbumintest).For confirmation, random/"spot" urine albumin/creatinine ratio (mg ofalbumin/g of creatinine) is the preferred method.

Detection of early diabetic nephropathy. Predictor of increasedcardiovascular risk. Value of this test to detect early stages ofother glomerulopathies, and in patients with hypertension ormetabolic syndrome (syndrome X) not yet fully established.

Quantitation of Overt Proteinuria

Random/"spot" urine protein/urine creatinine ratio is the preferred method.Avoids the need for cumbersome 24 hr urine collection.

Differential diagnosis of various renal diseases depending onamount of protein excreted (see Table 2) and assessing theseverity of renal disease.

Separate day time (upright) and night time (recumbent) collection ofurine for protein measurement

Ruling out postural proteinuria. Random urine protein/urinecreatinine ratio of day and night samples can not be used todiagnose postural proteinuria.'"

Serum creatinine/calculated glomerular filtration rate

Since the serum creatinine level is proportional to the muscle mass of theindividual, even a serum creatinine level in the "normal" range mightindicate impaired renal function in nonmuscular individuals. Thus, theglomerular filtration rate should always be calculated using the serumcreatinine ''̂ **

Assessing severity of renal disease. Serum creatinine level2:1.2 mg/dL in an adult female and a 1.4 mg/dL in an adultmale, or a calculated creatinine clearance <90 mL/minshould be considered as renal failure.

Serum total protein, albumin, and lipoproteins Assessing the effects of proteinuria on the level of proteins andlipids in the blood.

more expensive and might miss the presence of other proteinssuch as globulins, light chains, and protein markers of tubulardamage (j3-2 microglobulin). In addition, since a portion ofthe fdtered albumin is broken down into unmeasured metab-olites, specific albumin tests may underestimate the magni-tude of albuminuria. Tables 4 and 5 show the tests used toevaluate proteinuric patients.

Occasionally, carcinomas and lymphomas may presentinitially with overt proteinuria.^' However, the yield of can-cer screening in the evaluation of overt proteinuria is low andonly age-appropriate annual cancer screening is warranted.

Indications for Nephrology Consultationin Overtly Proteinuric Patients

Nephrology evaluation is indicated in overtly proteinuricpatients with a random urine protein/urine creatinine ratio> 1, and (even if the ratio is between 0.2 and 1.0) those withglomerular filtration rate <60 mL/min (or serum creatinines 1.2 in women and > 1.4 mg/dL in men), hypertension, his-tory of systemic diseases (eg, diabetes mellitus, systemic lu-

pus erythematosus), use of medications or illicit drugs knownto cause proteinuria (gold, penicillamine, captopril, chronicuse of nonsteroidal antiinflammatory drugs, heroin), familyhistory of renal disease or, if required for insurance/employ-ment purposes. The nephrology consultant can help to decideif renal biopsy and immunosuppressive therapy are indicated.Measures to reduce the magnitude of proteinuria and slowingthe progression of renal failure are best undertaken with theinput of a nephrologist. Even if it is determined that there isno immediate indication for nephrology referral, periodicmonitoring of the blood pressure, serum creatinine and therandom urine protein/urine creatinine ratio at least annually iswarranted. If any of these parameters worsen, nephrologyevaluation is indicated.

Treatment of ProteinuriaThere are three aspects to the treatment of the proteinuric

patient: corticosteroid and immunosuppressive therapy of thecausative renal disorder, correcting the clinical effects of pro-teinuria, and measures to reduce the quantity of urinary protein.


CME Topic

Table 5. Laboratory studies in the evaluation of proteinuria: tests for identifying etiology of causative renal disease"

Type of test Purpose of the test

Blood glucose; glycosylated hemoglobin

Serum immunoelectrophoresis and monoclonal protein evaluation;urine immunoelectrophoresis and light chain typing

Tests for autoimmune disorders:Antinuclear antibody (ANA), anti-neutrophil cytoplasmic antibody

(ANCA),* anti-glomerular basement membrane antibody,*"rheumatoid factor/cryoglobulins,* serum C3 and C4 complements

Detection of diabetes mellitus, the most common cause of overtproteinuria and chronic kidney disease.

Detection of multiple myeloma and other paraproteinemic states.To be included in evaluation of patients >45 years old.

Detection of systemic lupus erythematosus, vasculitides, systemicsclerosis, Sjogren syndrome, antiglomerular basement membraneantibody disease, cryoglobulinemia, hypocomplementemic renaldiseases (lupus nephritis; membranoproliferative, post-infectiousand cryoglobulinemie glomerulonephdtis).

Tests for infectious disorders:Hepatitis B surface antigen. Hepatitis C antibody, Human

Immunodeficiency Virus (HIV) antibody, antistreptolysinantibody,* VDRL test

Detection of Hepatitis-B, Hepatitis-C or HIV-associated renaldisease, poststreptococcal glomerulonephdtis, glomerulopathy insecondary syphilis.

"VDRL, Venerat Disease Research Laboratory,

''Indicated in patients with "nephritic " urine sediment (presence red blood cells ± red blood ceil casts).

Immunosuppressive therapy of the causative renaldisorder

Therapy aitned at the immunologic mechanisms causingproteinuric renal disorders is not discussed further here be-cause it is usually undertaken with the assistance of a neph-rologist. Evidence-based recommendations on this subjecthave been ^" '̂

Treatment of the clinical effects of proteinuriaThis addresses the problems of edema, hyperlipidemia,

thromboembolism, and infection associated with heavy pro-teinuria.^ Edema requires dietary sodium restriction and theuse of diuretics. Hyperlipidemia associated with nephroticsyndrome warrants treatment with a statin for hypercholes-terolemia or fibrate for hypertriglyceridemia. In addition toits cardiovascular benefits, such therapy may also slow theloss of renal function. "'^'-^^ Nephrologists differ in their ap-proach to the treatment of the hypercoagulability associatedwith heavy proteinuria: prophylactic anticoagulation in allpatients with a serum albumin level <2.5 g/dL, versus allmarkedly hypoalbuminemic patients with membranous ne-phropathy (the glomerulopathy with the highest risk of throm-boembolism), versus anticoagulation therapy only after theoccurrence of a thromboembolic event.'̂ Once initiated, anti-coagulation needs to be continued as long as heavy protein-uria persists.

Measures to reduce microalbuminuria and overtproteinuria

Reduction of microalbuminuria with an ACE-I or ARBmay decrease the subsequent development of overt protein-uria and clinical diabetic nephropathy.'*''""^ In fact, the "pro-

phylactic" treatment of even normoalbuminuric diabetics withdrugs blocking the renin-angiotensin system has been sug-gested.** -̂'̂ ''

In overtly proteinuric patients, measures to reduce pro-teinuria are worthwhile even in the absence of the clinicalfeatures of the nephrotic syndrome, because reduction of pro-teinuria retards the rate of progression of chronic renal fail-yj.g 16-19,21 Dietary protein restriction^^"^'' and ACE-I and/orARB therapy^^"^^ have been shown to reduce proteinuria.While there are no controlled studies in patients with renaldisease, intuitively, pharmacologic blockade of the renin-an-giotensin system may also be protective against the cardio-vascular problems highly prevalent in patients with chronickidney disease.

Most long-term trials in type 1 diabetic nephropathy andnondiabetic renal diseases have been with ACE-Is, and withARBs in type 2 diabetic nephropathy. Based on these studies,it has been recommended that patients with type 1 diabeticnephropathy and nondiabetie renal diseases are best treatedwith an ACE-I and type 2 diabetics with an ARB. However,several short-term and a few long-term comparative studieshave shown these two classes of drugs to have equal efficacyin patients with chronic kidney disease.^°'̂ ^~^° The decisionto select an ACE-I versus an ARB for initial therapy is in-fluenced by a number of factors besides the type of renaldisease. In patients with ACE-I-indueed cough or angio-edema, only an ARB can be used beeause these side effectsare extremely rare with the latter. Captopril, enalapril, andlisinopril are available in generic form, and cost consider-ations may dictate the use of a generic drug. ARBs appear toincrease the serum potassium less than the ACE-Is,^' but theutility of substituting the former for the latter drug when



hyperkalemia limits therapy has not been established. Thebenefits of both these groups of drugs in chronic kidneydisease is probably a class-effect since the different ACE-Isused in the landmark trials were equally renoprotective,^^"24,30 and irbesartan and losartan have produced similar resultsin type 2 diabetic nephropathy.^''^^ In general, a drug per-mitting once-a-day dosing should be chosen to improve com-pliance. Table 6 outlines the selection/adjustment of antihy-pertensive drugs to reduce proteinuria. Measures to deal withthe adverse effects of drugs blocking the renin-angiotensinsystem are shown in Table 7. "

The relative importance of blood pressure control (whichmight by itself reduce proteinuria) and proteinuria reduction

Table 6. Use of different groups of antihypertensivemedications for blood pressure control, and reductionof microalbuminuria or overt proteinuria

Goals:

a) Normoalbuminuria or at least 50% reduction in albuminuria inmicroalbuminuric patients.

b) Daily protein excretion of <5OO-IOOO mg or random urine protein/urine creatinine ratio of <0.5-1.0 in patients with overt proteinuria, orat least a 50% reduction of baseline '"''^^'

c) Blood pressure; Systolic <130 and diastolic <80 mm Hg (JointNational Commission-7 recommendation'^'" and <125 systolic anddiastolic <75 mm Hg (National Kidney Foundationrecommendation)."

Initial Therapy:

i) Initiate therapy with an angiotensin-converting enzyme inhibitor (ACE-I) in patients with type 1 diabetic nephropathy or nondiabetic renaldisease, and an angiotensin-receptor blocker (ARB) in patients withtype 2 diabetes (see text for criteria for selection of a drug from one ofthe two classes).

ii) Dietary salt restriction and/or addition of a diuretic: potentiatesantiproteinuric and antihypertensive effects of renin-angiotensin systemblocking drugs.'"*

iii) Monthly increase of the dose of these medications until bloodpressure and proteinuria goals achieved (watching for symptomatichypotension) or maximal recommended antihypertensive dose isreached.

If blood pressure and/or proteinuria goals not achieved despitemaximal doses of ACE-I or ARB, in combination witb a diuretic:

i) Addition of nondihydropyridine calcium channel blockers (diltiazem orverapamil) and/or beta-blocker may decrease proteinuria in addition toimproving blood pressure control. Dihydropyridine-calcium channelblockers (nifidepine, amlodipine) may increase proteinuria,'''"" but maybe needed to achieve control of blood pressure.

ii) In severely hypertensive patients (systolic a 160 and/or diastolic £90mm Hg), this step-wise approach is inappropriate and combinationtherapy with a drug from each of the above-mentioned groups mightbe required right at the start. Most patients will require the combineduse of 3 to 4 classes of drugs to achieve blood pressure andproteinuria control."

iii) Other options to reduce proteinuria include using an ACE-1 or ARBin higher than the maximum doses recommended for bloodpressure control,"*'" combination therapy with these two classes ofdrugs,'"'''*""'*' addition of spironolactone**" or a nonsteroidalantiinflammatory drug.^ Such therapies greatly increase the risk ofacute elevations of serum potassium,*"* and creatinine,'" and requirevery close monitoring of these levels.

in affording renoprotection continues to be debated.'̂ •̂̂ •' Pro-teinuria targets may not always be achieved despite maximaltherapy. In such patients, it should be ensured that at least theblood pressure goals are achieved. The control of both sys-tolic and diastolie blood pressure to recommended levels isimportant. Besides blood pressure control and reduction ofproteinuria, other measures also help to ameliorate the pro-gression of renal failure: dietary protein restriction, optimaldiabetes control, correction of calcium/phosphorous levels,treatment of hyperlipidemia, correction of anemia, smokingcessation, and avoidance of nephrotoxic agents (nonsteroidalanti inflammatory agents, cyclooxygenase-2 inhibitors, ami-noglycosides, radio-contrast)."•'^-^'

Renin-angiotensin system blockade may not be unique inconferring renoprotection. A large study showed that aj3-blocker and an ACE-I were equally effective in diabeticnephropathy.''' In the African-American Study of Kidney Dis-ease, the amlodipine arm was terminated early because it wasinferior to ramipril in slowing the progression of renal failure,but the double-blind comparison of ramipril to a /3-blocker iscontinuing.29

ConclusionMicroalbuminuria and overt proteinuria persisting on re-

testing the urine should be regarded as potentially seriousabnormalities. The quantity of protein excreted per day, theserum creatinine level, and the calculated glomerular filtra-tion rate determine the severity of the underlying renal dis-order. Patients with overt proteinuria, >1 g/d (or randomurine protein/urine creatinine ratio > 1.0) or associated withreduced renal function will benefit from evaluation by a neph-rologist. Even with normal renal function and overt protein-uria of 0.2 to 1 g/d, nephrology consultation is indicated ifhypertension, systemic diseases which comtnonly involve thekidneys (eg, diabetes mellitus, systemic lupus erythemato-sus), a history of use of medications or illicit drugs known tocause proteinuria, or a family history of renal disease ispresent. Type 1 diabetes of more than 5 years' duration, andtype 2 diabetes irrespective of known duration, are indica-tions for annual testing for microalbuminuria. Importantly,therapy in microalbuminuric or overtly proteinuric patientsshould aim for blood pressure control to a level < 130 to 125mm Hg systolic, and diastolic <80 to 75 mm Hg, and themaximum possible reduction of microalbuminuria and overtproteinuria to retard the development/progression of chronickidney disease. Mieroalbuminuric and overtly proteinuricpatients have a high risk of developing cardiovascular dis-ease. In addition to focusing on renal disease, close attentionshould be paid to correcting all risk factors for cardiovasculardisease in this patient population. The cornerstone of suchrenal and cardiovascular protective therapy is the use ofACE-ls and/or ARBs.


CME Topic

Table 7. Common problems encountered during the use of ACE-Is ARBs in patients with chronic kidney disease"

Problem Monitoring and therapy

Hyperkalemia

Caused by decreased aldosterone levels resulting from blockade of therenin-angiotensin system. This leads to decreased urinary and colonicexcretion of potassium.

Monitor serum potassium levels closely during initial 3-4 weeks oftherapy and after each dose increase. Aim for serum potassium <5.5mEq/L.

Instruct patient about the need for dietary potassium restriction andavoidance of potassium-containing salt substitutes.

Avoid potassium supplements/potassium-sparing diuretics.

Addition of a loop-diuretic to increase urinary potassium exeretion.

Value of changing from ACE-I to ARB to reduee hyperkalemia" has notbeen established.

Daily doses of a cation-exchange resin (sodium polystyrene sulfonate).

Increase in serum creatinine level

Caused by decreased glomerular filtration rate due to deereasedintraglomerular hydrostatic pressure resulting from glomerular efferentarteriolar dilatation when angiotensin II level is deereased orangiotensin II action is blocked by these two groups of drugs. Usuallyoccurs within 2 to 3 weeks of starting therapy.'"

Monitor serum creatinine level elosely during initial 3-4 weeks oftherapy and after each dose increase. Up to a 30% increase is expected.Stop therapy only if >30% inerease of serum ereatinine occurs.'"

ACE-I-induced cough (10-15% of patients) or angioedema (<5% ofpatients)

Due to elevated kinin levels resulting from inhibition of the eonvertingenzyme which catabolizes kinins into inactive metabolites.

Caution patient to watch out for these symptoms. Switch to an ARB.These side effects are very rare with ARBs.

Worsening anemia of chronic kidney disease

Due to decreased erythropoietin level or effect on bone marrow." Initiate erythropoietin therapy if hemoglobin level < 11 g/dL.

"ACE-I, angiolensin-converling enzyme inhibitors: ARB, angiotensin receptor blockers.

References1. Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, de-

tection, elimination (PARADE): a position paper of the National KidneyFoundation. Am J Kidney Dis 1999;33:1004-1010.

2. Orth SR, Ritz E. The nephrotie syndrome. N EngI J Med 1998;338:1202-1211.

3. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies.N EnglJ Med 1998;339:I448-1456.

4. Abbate M, Benigni A, Bertani T, et al. Nephrotoxicity of increasedglomerular protein traffic. Nephrol Dial Transplant 1999;14:304-312.

5. Gerstein HC, Mann JFE, Yi Q, et al. Albuminuria and the risk of car-diovascular events, death, and heart failure in diabetie and nondiabeticindividuals. JAMA 2001;286:421-426.

6. Yuyun MF, Khaw K-T, Luben R, et al. A prospective study of mi-croalbuminuria and incident coronary heart disease and its prognostiesignificance in a British population—the EPIC-Norfolk Study. Am JEpidemiol 2004;159:284-293.

7. Coresh J, Astor BC, Greene T, et al. Prevalenee of ehronie kidneydisease and decreased kidney function in the adult US population. ThirdNational Health and Nutrition Examination Survey. Am J Kidney Dis2OO3;41:1-I2.

8. Fuller CE, Threatte GA, Henry JB. Basie examination of urine, in HenryJB (ed): Clinical Diagnosis and Management by Laboratory Method-.V. Philadelphia, WB Saunders Co, 2001, ed 20, pp 373-376.

9. Hcbert SC, Reilly RF Jr, Kriz W. Structural-functional relationships inthe kidney, in Sehrier RW (ed): Diseases of the Kidney and UrinaryTract, Philadelphia, Lippincott, Williams and Wilkins, 2001, ed 7, pp3-57.

10. Lafayette RA, Pcrrone RD, Levey AS. Laboratory evaluation of renalfunetion, in Sehrier RW (ed): Diseases of the Kidney and Urinary Tract,Philadelphia, Lippincott, Williams and Wilkins, 2001, ed 7, pp 333-369.

11. K/DOQl clinical practice guidelines for chronic kidney disease: evalu-ation, classification and stratification. Am J Kidnev Dis 2002;39(suppl2):S1-S266.

12. Mundel P, Shankland SJ. Podoeyte physiology and response to injury.JAm Soc Nephrol 2OO2;I3:3OO5-3O15.

13. Devarajan P. Meehanisms of orthostatie proteinuria: lessons from a trans-plant donor. JAm Soc Nephrol 1993;4:36-39.

14. Ginsberg JM, Chang BS, Matarese RA, et al. Use of single voided urinesamples to estimate quantitative proteinuria. N EngI J Med 1983;309:1543-1546.

15. Rodby RA, Rohde RD, Sharon Z, et al. The urine protein to creatinineratio as a predictor of 24-hour urine protein excretion in type 1 diabeticpatients with nephropathy. The Collaborative Study Group. Am J KidneyDis 1995;26:904-909.

16. Taal MW, Brenner BM. Renoproteetive benefits of RAS inhibition:from ACE I to angiotensin II antagonists. Kidney Int 2000;57:1803-1817.

17. Brenner BM. Remission of renal disease: reeounting the challenge, ae-quiring the goal. J Clin Invest 2002;l 10:1753-1758.

18. Campbell RC, Ruggenenti P, Remuzzi G. Halting the progression ofchronic nephropathy. 7/4m Soc Nephrol 2002;13:S190-SI95.

19. Brenner BM. Retarding the progression of renal disease. Kidney Int2003;64:370-378.

20. Brewster UC, Perazella MA. The renin-angiotensin-aldosterone systemand the kidney: effects on kidney disease. Am J Med 2004; 116:263-272.

Southern Medicat Journat • Volume 97, Number 10, October 2004 977


21. Wilmer WA, Rovin BH, Hebert CJ, et al. Management of glomerularproteinuria: a commentary. J Am Soc Nephrol 2003; 14:3217-3232.

22. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-coiiverting-enzyme inhibition on diabetic nephropathy. The Collabora-tive Study Group. N EnglJ Med I993;329:1456-1462.

23. Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-convert-ing-enzyme inhibitor benazepril on the progression of chronic renalinsufficiency. N EnglJ Med 1996;334:939-945.

24. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefro-logia). Randomised placebo-controlled trial of effect of ramipril on de-cline in glomerular filtration rate and risk of terminal renal failure inproteinuric, non-diabetie nephropathy. Lancet 1997;349:1857-1863.

25. Ruggenenti P, Pema A, Gherardi G, et al. For the Gruppo Italiano diStudi Epidemiologici in Nefrologia (GISEN). Renal function and re-quirement for dialysis in chronic nephropathy patients on long-termramipril: REIN follow-up trial. Ramipril Efficacy in Nephropathy. Lan-cet 1998;352:1252-I256.

26. Ruggenenti P, Pema A, Benini AR, et al. For the Gruppo Italiano diStudi Epidemiologici in Nefrologia (GISEN): In chronic nephropathiesprolonged ACE inhibition can induce remission: dynamics of time-de-pendent changes in GVK. J Am Soc Nephrol 1999; 10:997-1006.

27. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of theangiotensin-receptor antagonist irbesartan in patients with nephropathydue to type 2 diabetes. N EngI J Med 2001 ;345:851-860.

28. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renaland cardiovascular outcomes in patients with type 2 diabetes and ne-phropathy. A' Engl J Med 2001;345:861-869.

29. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs. amiodipineon renal outcomes in hypertensive nephrosclerosis: a randomized eon-trolled trial. JAMA 2001;285:27l9-2728.

30. Nakao N, Yoshimura A, Morita H, et al. Combination treatment ofangiotensin II receptor bloeker and angiotensin-converting enzyme in-hibitor in nondiabetie renal disease (COOPERATE): A randomized eon-trolled trial. Lancet 2003;361:l 17-124.

31. Schrier RW, Estacio RO. The effect of angiotensin-converting enzymeinhibitors on the progression of nondiabetie renal disease: a pooledanalysis of individual-patient data from 11 randomized, controlled trials.Ann Intern Merf 2OO1;135:I38-139.

32. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-eonverting enzymeinhibitors and progression of nondiabetie renal disease. A meta-analysisof patient-level data. Ann Intern Med 2001;135:73-87.

33. Jafar TH, Schmid CH, Levey AS. Effect of angiotensin-eonverting en-zyme inhibitors on progression of nondiabetie renal disease. Ann InternMerf 2002; 137:298-299.

34. Jafar TH, Stark PC, Sehmid CH, et al. Progression of chronic kidneydisease: the role of blood pressure eontrol, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann InternMerf 2003; 139:244-252.

35. Ruggenenti P, Pema A, Gherardi G, et al. Renoprotective properties ofACE-inhibition in non-diabetie nephropathies with non-nephrotic pro-teinuria. Lancet 1999;354:359-364.

36. Eddy AA, Giachelli CM. Renal expression of genes that promote inter-stitial inflammation and fibrosis in rats with protein-overload protein-uria. Kidney Int 1995;47:1546-1557.

37. Abbate M, Zoja C, Coma D, et al. In progressive nephropathies, over-load of tubular cells with filtered proteins translates glomerular perme-ability dysfunction into cellular signals of interstitial inflammation. J AmSoc Nephrol 1998;9:1213-1224.

38. Zoja C, Donadelli R, Colleoni S, et al. Protein overload stimulates RAN-TES production by proximal tubular eells depending on NF-kappa Bactivation. Kidney Int 1998;53:1608-1615.

39. Donadelli R, Zanchi C, Morigi M, et al. Protein overload induces frac-talkine upregulation in proximal tubular cells through nuelear faetor kB-and p38 mitogen-aetivated protein kinase-dependent pathways. .//4m SocNephrol 2003; 14:2436-2446.

40. Mogensen CE, Christensen CK. Predieting diabetic nephropathy in in-sulin-dependent patients. N Engl J Med 1984;311:89-93.

41. Messent JW, Elliott TG, Hill RD, et al. Prognostic significance of mi-eroalbuminuria in insulin-dependent diabetes mellitus: a twenty-threeyear follow-up study. Kidney Int 1992;41:836-839.

42. The Diabetes Control and Complications (DCCT) Research Group. Ef-fect of intensive therapy on the development and progression of diabetienephropathy in the Diabetes Control and Complieations Trial. Kidney Int1995;47:1703-1720.

43. The Mieroalbuminuria Study Group. Captopril reduces the risk of ne-phropathy in IDDM patients with microalbuminuria. Diahetologia 1996;39:587-593.

44. The ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should allpatients with type 1 diabetes mellitus and microalbuminuria receiveangiotensin-eonverting enzyme inhibitors? A meta-analysis of individ-ual patient data. Ann Intern Med 2OOI;l34:37O-379.

45. Parving H-H, Lehnert H, Broehner-Mortensen J, et al. The effect ofirbesartan on the development of diabetic nephropathy in patients withtype 2 diabetes. W Cng/^ A/eJ 2001;345:870-878.

46. Perkins BA, Ficociello LH, Silva KH, et al. Regression of microalbu-minuria in type 1 diabetes. N Engl J Med 2003;348:2285-2293.

47. Pedrinelli R, DeH'Omo G, Penno G, et al. Microalbuminuria, a param-eter independent of metabolic influences in hypertensive men. J Hvper-teni2003;21:l 163-1169.

48. Palaniappan L, Carnethon M, Fortmann SP. Assoeiation between mi-eroalbuminuria and the metabolic syndrome: NHANES III. Am J Hy-

2003; 16:952-958.

49. U.S. Renal Data System. USRDS 2001 Annual Data Report: atlas ofend-stage renal disease in the United States. National Institute of Dia-betes and Digestive and Kidney Diseases 2001, Bethesda, MD.

50. Hostetter TH. Prevention of end-stage renal disease due to type 2 dia-betes. N Engl J Med 2001;345:910-912.

51. Haroun MK, Jaar BG, Hoffman SC, et al. Risk factors for chronic kidneydisease: a prospective study of 23,534 men and women in WashingtonCounty, Maryland. 7/)m Soc Nephrol 2003;l4:2934-2941.

52. Levey AS, Beto JA, Coronado BE, et al: Controlling the cpidemie ofeardiovaseular disease in ehronic renal disease: What do we know?Where do we go from here? National Kidney Foundation Task Force onCardiovaseular Disease. Am J Kidney Dis 1998;32:853-906

53. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and car-diovascular disease in patients with type 2 diabetes. A' Engl J Med2003;348:383-393.

54. Bennett PH, Haffner S, Kasiske BL, et al. Screening and management ofmieroalbuminuria in patients with diabetes mellitus: recommendationsto the Scientific Advisory Board of the National Kidney Foundationfrom an ad hoe Committee of the Council on Diabetes Mellitus of theNational Kidney Foundation. Am J Kidney Dis 1995;25:107-l 12.

55. American Diabetes Association clinical practice recommendations 2003:diabetic nephropathy. Diabetes Care 2003;26(suppl I):S94-S98.

56. Preventive Services Task Force, Guide to elinieal preventive services.Report of the U.S. Preventive Serviees Task Force. Baltimore, Williamsand Wilkins 1996, ed 2.

57. Coekcroft DW, Gault MH. Prediction of creatinine elearance from se-mm creatinine. Nephron 1976;I6:31—41.

58. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method toestimate glomerular filtration rate from semm creatinine: a new predic-tion equation. Ann Intern Med 1999;130:461-470.

59. Roneo PM. Paraneoplastic glomemlopathies: new insights into an oldentity. Kidney Int 1999;56:355-377.

60. Management of glomemlonephritis. Kidney Int 1999;55(suppl 7O):S1-S62.

61. Appel GB, Glassock RJ. Glomerular, vascular, tubulo-interstitial andgenetie diseases. American Society of Nephrology. NephSAP (Nephrol-


CME Topic

ogy Self-Assessment Program), Volume I Syllabus, July 2002; 13—46.(Accessed April 28, 2004 at http://www.asn-online.org).

62. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on theprogression of renal disease: a meta-analysis. Kidney Int 2001;59:260-269.

63. Ravid M, Brosh D, Levi Z, et al. Use of enalapril to attenuate decline inrenal function in normotensive, normoalbuminuric patients with type 2diabetes mellitus: a randomized, controlled trial. Ann Intern Med 1998;128:982-988.

64. Golan L, Birkmeyer JD, Welch HG. The cost-effectiveness of treatingall patients with type 2 diabetes with angiotensin-converting enzymeInhibitors. Ann Intern Med 1999; 131:660-667.

65. Klahr S, Levey AS, Beck GJ, et al. Effects of dietary protein restrictionand blood pressure control on the progression of chronic renal disease.N EnglJ Med 1994;330:877-884.

66. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, pro-teinuria and the progression of renal disease: The Modification of Dietin Renal Disease Study. Ann Intern Med 1995;123:754-762.

67. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction and theprogression of chronic renal disease: what have all the results of theMDRD study shown? J ^ m Soc Nephrol 1999; 10:2426-2439.

68. Hilgers ICF, Mann JFE. ACE inhibitors versus ATI receptor antagonistsin patients with chronic kidney disease. J Am Soc Nephrol 2002; 13:1100-1108.

69. Zandbergen AAM, Baggen MGA, Lamberts SWJ, et al. Effect of losar-tan on microalbuminuria in normotensive patients with type 2 diabetesmellitus: a randomized clinical trial. Ann Intern Med 2003;139:90-96.

70. Lacourciere Y, Belanger A, Godin G, et al. Long-term comparison oflosartan and enalapril on kidney function in hypertensive type 2 diabet-ics with early nephropathy. Kidney Int 2000;58:762-769.

71. Bakris GL, Siomos M, Richardson D, et al. AGE inhibition or angio-tensin receptor blockade: impact on potassium in renal failure. Kidneyhit 2000;58:2084-2092.

72. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of theJoint National Gommittee on prevention, detection, evaluation and treat-ment of high blood pressure: the JNG 7 report. JAMA 2003;289:2560-2571.

73. Ghobanian AV, Bakris GL, Black HR. et al. The National High BloodPressure Education Program Seventh Report of the Joint National Gom-mittee on Prevention, Detection, Evaluation, and Treatment of HighBlood Pressure. Hypertension 2OO3;42:I2O6-1252.

74. Buter H, Hemmeldeer MH, Navis G et al. The blunting of the antipro-teinuric efficacy of AGE inhibition can be restored by hydrochlorthia-zide. Nephrol Dial Transplant 1998; 13:1682-1685.

75. Smith AG, Toto R, Bakris GL. Differential effects of calcium channelblockers on size selectivity of proteinuria in diabetic glomerulopathy.Kidney Int l998;54:889-896.

76. Ruggenenti P, Pema A, Benini R, et al. Effects of dihydropyridinecalcium channel blockers, angiotensin-converting enzyme inhibition andblood pressure control on chronic nondiabetic nephropathies. J Am SocNephrol 1998;9:2096-2101.

77. Bakris GL. A practical approach to achieving recommended blood pres-sure goals in diabetic patients. Arch Intern Med 2001;161:2661-2667.

78. Laverman GD, Andersen S, Rossing P, et al. Dose-dependent reductionof proteinuria by losartan does not require reduction of blood pressure.JAm Soc Nephrol 2002;13:265A.

79. Piccoli A, Pillon L. The antiproteinuric effect of high-dose ramipril: stillan open question. Kidney Int 2003;63:769-770.

80. Mogensen GE, Neldam S, Tikkanen 1, et al. Randomised controlled trialof dual blockade of renin-angiotensin system in patients with hyperten-sion, microalbuminuria, and non-insulin dependent diabetes: the cande-sartan and lisinopril microalbuminuria (GALM) study. SM/2000;321:1440-1444.

81. Jacobsen P, Andersen S, Jensen BR, et al. Additive effect of AGEinhibition and angiotensin II receptor blockade in type 1 diabetic patientswith diabetic nephropathy. J Am Soc Nephrol 2003; 14:992-999.

82. Jacobsen P, Andersen S, Rossing K, et al. Dual blockade of the renin-angiotensin system versus maximal recommended dose AGE inhibitionin diabetic nephropathy. Kidney Int 2003;63:1874-1880.

83. Gampbell R, Sangalli F, Perticucci E, et al. Effects of combined AGEinhibitor and angiotensin 11 antagonist treatment in human chronic ne-phropathies. Kidney Int 2003;63:1094-1103.

84. Rossing K, Ghristensen PK, Jensen BR, et al. Dual blockade of renin-angiotensin system in diabetic nephropathy: a randomized double-blindcrossover study. Diabetes Care 2002;25:95-100.

85. Russo D, Minutolo R, Pisani A, et al. Goadministration of losartan andenalapril exerts additive antiproteinuric effect in IgA nephropathy. Am JKidney Dis 200\;3SM-25.

86. Ruilope LM, Aldigier JG, Ponticelli G, et al. Safety of combination ofvalsartan and benazepril in patients with chronic kidney disease. Euro-pean Group for the Investigation of Valsartan in Ghronic Renal Disease.J Hypertens 2000; 18:89-95.

87. Agarwal R. Add on angiotensin receptor blockade with maximal AGEinhibition. Kidney Int 2001;59:2282-2289.

88. Ghrysostomou A, Becker G. Spironolactone in addition to AGE inhibi-tion to reduce proteinuria in patients with chronic kidney disease. A' EngIy We</2001;345:925-926.

89. Schepkens H, Vanholder R, Billiouw JM, et al. Life-threatening hyper-kalemia during combined therapy with angiotensin-converting enzymeinhibitors and spironolactone: analysis of 25 cases. Am J Med 2001; 110:438-441.

90. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associ-ated elevations in serum creatinine. Is this a cause for concern?. ArchIntern Med 2000; 160:685-693.

91. Dhondt AW, Vanholder RG, Ringoir SM. Angiotensin-converting en-zyme inhibitors and higher erythropoietin requirement in chronic hemo-dialysis patients. Nephrol Dial Transplant I995;1O:21O7-21O9.

92. Vogt L, Navis G, de Zeeuw D. Renoprotection: a matter of blood pres-sure reduction or agent-characteristics?. J Am Soc Nephrol 2002; 13:S202-S207.

93. Locatelli F, Del Vecchio L, D'Amico M, et al. Is it the agent or the bloodpressure level that matters for renal protection in chronic nephropathies?.JAm Soc Nephrol 2002;13:S196-S201.

94. UK Prospective Diabetes Study Group: Efficacy of atenolol and capto-pril in reducing risk of maerovascular and microvascular complicationsin type 2 diabetes: UICPDS 39. BMJ 1998;317:713-720.


Documents

Proteinuria and Microalbuminuria in Adults; Significance, Evaluation