Nephropathy is one of the most common

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1 THE EVALUATION OF DIABETIC NEPHROPATHY: PREVENTING COMPLICATIONS Katherine Tuttle, MD * ABSTRACT Nephropathy is one of the most common diabetic microvascular complications. Without specific intervention, patients with diabetes with microalbuminuria can progress to end-stage renal disease (ESRD) within 10 to 20 years. At greater risk are ethnic minority populations that are disproportionately affected by diabetic nephropathy and subsequent complications. Early detection and treatment can attenuate the progression of nephropathy to ESRD, and a variety of screening techniques are used to this end. Microalbuminuria has been recognized as an early predictor of nephropathy and has become an important screening target. There are 3 common methods of screening used to detect microalbuminuria: measurement of albumin-tocreatinine ratio in random spot collection, a 24- hour urine collection with creatinine, and a timed (4 hour or overnight) collection. Glomerular filtration rate (GFR) may also predict progression of nephropathy because it can indicate underlying glomerular hyperfiltration and hypertension. Kidney function is best estimated by GFR, and the stages of chronic kidney disease are determined by respective GFR levels. GFR can be estimated with predictive equations or a 24-hour urine sample or measured directly using insulin. The National Kidney Foundation and the American Diabetes Association have developed clinical guidelines that detail a screening protocol to be used for patients with diabetes. This article examines the current guidelines and the issues surrounding *Director of Research, The Heart Institute of Spokane, Spokane, Washington. Address correspondence to: Katherine Tuttle, MD, 122 W 7th Avenue, Suite 230, Spokane, WA ktuttle@this.org. screening for diabetic nephropathy, including the link with diabetic retinopathy, discusses the prediction of progression, and also provides an algorithm for primary care diagnosis of kidney disease. (Adv Stud Med. 2005;5(1A):S20-S27) Nephropathy is one of the most common diabetic microvascular complications. Between 20% and 30% 1-3 of patients with type 1 or type 2 diabetes mellitus will have signs or symptoms of diabetic nephropathy during their lifetimes, depending on factors, such as ethnicity, age, and severity of diabetic retinopathy. Ethnic minority populations are disproportionately affected by diabetic nephropathy, renal failure, and end-stage renal disease (ESRD). 4,5 African Americans have 3.9 times the relative risk of renal failure as does the white population; Native Americans, 2.9 times; and Asians, 1.6 times. 4,6 Specific populations, such as the Pima Indians of Arizona, are at particular risk because they have a much higher incidence of diabetic nephropathy and the disease progresses more rapidly to ERSD. 7 Without specific interventions, 50% of patients with type 1 diabetes mellitus and with overt diabetic nephropathy (urine protein 300 mg/24 hours) progress to ESRD within 10 years of onset, whereas more than 75% progress to ESRD over a 20-year period. 8 Although fewer patients with type 2 diabetes mellitus progress to ESRD over a 20-year period (20%), the numbers are still substantial. 8 Fewer patients progress to ESRD, in part, because of the competing mortality of cardiovascular disease. Therefore, as cardiovascular mortality rates decline, even more persons with type 2 diabetes mellitus can be expected to progress to renal failure. 8 As the overall incidence of S20 Vol. 5 (1A) January 2005

2 ESRD continues to increase, diabetes mellitus is the greatest cause for this increase (Figure 1). 8,9 Fortunately, study evidence continues to show that the course of diabetic nephropathy can be modified by early intervention, or perhaps even reversed This evidence underscores the merit of screening atrisk populations to identify renal dysfunction and to intervene at the earliest possible stages. NATURAL HISTORY OF DIABETIC NEPHROPATHY Because microalbuminuria is recognized as an early predictor of diabetic nephropathy in addition to cardiovascular disease, it has become an important target for screening. The 3 most common methods of screening for microalbuminuria are measurement of the albumin-to-creatinine ratio in random spot collection, a 24-hour urine collection with creatinine, allowing simultaneous measurement of creatinine clearance, and a timed (4 hour or overnight) collection. 8 The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) 12 recommends screening, using standard or albumin-specific dipsticks or protein-to-creatinine or albumin-to-creatinine ratio. Reference ranges and abnormal ranges for albumin excretion are shown in Table Microalbuminuria ( mg/day or mg/g creatinine, or 20 µg/min) is generally recognized as the earliest clinical evidence of diabetic nephropathy. 12 Without intervention, 80% of patients with type 1 diabetes mellitus who develop sustained microalbuminuria will experience an increase in the rate of excretion of urinary albumin by approximately 10% to 20% per year to overt diabetic nephropathy. 8 Over a period of 10 to 15 years, clinical albuminuria (>300 mg/24 hours or mg/g creatinine, or 200 µg/min) will develop along with hypertension. 8,12 Once overt diabetic nephropathy occurs, the glomerular filtration rate will decline over several years, although the rate of decline is highly variable, ranging from 2 to 20 ml min -1 yr A substantial number of patients with type 2 diabetes mellitus are diagnosed with microalbuminuria and with overt nephropathy upon initial examination or soon thereafter because diabetes mellitus and its associated risk factors, such as hypertension and dyslipidemia, have been present for many years before the diagnosis. 8 Without intervention, the prognosis for patients with type 2 diabetes mellitus and microalbuminuria is much the same. As in type 1 diabetes mellitus, the rate of decline in glomerular filtration from overt diabetic nephropathy (and the time period over which it occurs) to ESRD is highly variable. 8 SCREENING FOR DIABETIC NEPHROPATHY Figure 1. Increase in End-Stage Renal Disease Number of patients (in thousands) Number of patients Projection 95% confidence interval 326,217 86, ,407 98,953 Point prevalence R 2 = 99.7% Incidence R 2 = 99.8% 661, , Number of incident and point prevalent patients with end-stage renal disease projected to The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government. Table 1. Definitions of Albuminuria Urine Collection Overt Albuminuria Method Normal Microalbuminuria or Clinical Proteinuria 24-hour excretion <30 mg/day mg/day >300 mg/day Spot urine dipstick Albumin-specific dipstick <3 mg/dl >3 mg/dl N/A Spot urine <17 mg/g mg/g >250 mg/g albumin-to-creatinine ratio (men) (men) (men) (varies by gender*) 25 mg/g mg/g >355 mg/g (women) (women) (women) *Gender-specific cut-off values are from a single study. 19 Use of same cut-off value for men and women leads to higher values of prevalence for women than men. Current recommendations from the American Diabetes Association define cut-off values for spot urine albuminto-creatinine ratio for microalbuminuria and albuminuria as 30 and 300 mg/g, respectively, without regard to gender. 8 Reprinted with permission from National Kidney Foundation. Am J Kidney Dis. 2002;39:S1-S Advanced Studies in Medicine S21

3 Diagnosis of microalbuminuria should be based on 2 to 3 elevated levels within a 3- to 6-month period because there is a marked variability in day-to-day albumin excretion. 8 In addition, transient elevations in urinary albumin can result from short-term hyperglycemia, marked hypertension, acute febrile illness, or heart failure. 8 The measurement of albumin-to-creatinine ratio is the easiest method to administer in the office setting. This measurement generally provides accurate information, thus it is the preferred method as stated in the American Diabetes Association (ADA) Clinical Practice Guidelines. 8 First-void or other morning collections are advantageous 8,12 ; however, given the diurnal variations in albumin excretion, it is more important to consistently use the same timing for a patient to obtain accurate comparative measurements. A comparison of the advantages and disadvantages of the methods of urine collection for assessment of proteinuria is shown in Table The K/DOQI guidelines state that under most circumstances spot urine samples can be used to detect and monitor proteinuria in children and in adults (timed collection not often necessary). 12 The rationale behind the guideline is that the collection of a timed urine specimen is inconvenient and may be associated with errors. 12 Studies have shown a rough correlation between protein concentration in a spot urine sample and protein excretion rate, with the correlation of spot urine albumin to timed urine albumin ranging from 0.62 to 0.92; however, results can be affected by the patient s degree of hydration. 12 Spot urine protein-to-creatinine and albuminto-creatinine ratios overcome this limitation by correcting for variations in urinary concentrations caused by hydration (Tables 3 and 4). 12 When assays for microalbuminuria are not readily available, microalbuminuria dipsticks or reagent tablets can be used by trained personnel. Albumin-specific dipsticks detect albumin concentrations above the level of 3 to 4 mg/dl. 12 Several studies have compared the accuracy of a spot urine dipstick to timed urine albumin excretion in adults (Table 5). 12 However, stan- Table 2. Comparison of Methods of Urine Collection for Assessment of Proteinuria Random Urine for First Morning Urine Timed Overnight Urine Timed 24-Hour Albumin Albumin-to-Creatinine Ratio for Albumin-to-Creatinine Ratio for Albumin Excretion Excretion Advantages A good estimate of albumin excretion over the whole day Easy assays to perform in most laboratories Directly relates to published results of random A/C Easiest single sample collection A good estimate of overnight albumin excretion Easy assays to perform in most laboratories Directly relates to published results of first morning A/C Easier single sample collection Defines overnight albumin excretion Easy assay to perform in most laboratories Directly relates to published results of overnight excretion Easier collection of one or more samples Defines albumin over the entire 24 hours Easy assay to perform in most laboratories Directly relates to published results of 24-hour albumin excretion Disadvantages Lower creatinine excretion in women: higher values of A/C in women Lower creatinine excretion with age: higher values of A/C in older people Greater creatinine excretion in people of African descent: lower values of A/C Lower creatinine excretion in women: higher values of A/C in women Lower creatinine excretion with age: higher values of A/C in older people Greater creatinine excretion in people of African descent: lower values of A/C More complex collection of sample(s) More complex collection of sample(s) Frequent incomplete collections Frequent incomplete collections A/C = albumin-to-creatinine ratio. Reprinted with permission from National Kidney Foundation. Am J Kidney Dis. 2002;39:S1-S S22 Vol. 5 (1A) January 2005

4 dard urine dipsticks are too insensitive to detect microalbuminuria, but they are designed to be effective in detecting total protein concentrations above 10 to 20 mg/dl, 12 a level greater than the minimal indicator of microalbuminuria. K/DOQI guidelines state that screening for proteinuria with dipsticks is acceptable, but they also recommend confirmation of a positive dipstick reading of 1+ or greater with a quantitative measurement (ie, proteinto-creatinine ratio or albumin-to-creatinine ratio) within 3 months. 12 Patients who have 2 or more positive tests over the course of 1 to 2 weeks meet the diagnostic criteria for persistent proteinuria and should undergo further evaluation and management for chronic renal disease. 12 Dipstick tests are subject to false positives because of patient dehydration, hematuria, exercise, infection, and extremely alkaline urine that causes a reaction with the reagent pads on dipsticks. 12 Conversely, dipstick tests also are subject to false negatives as a result of excessive hydration and urine proteins other than albumin. When a dipstick result is inconsistent with clinical evaluation, a repeat analysis of urine with quantitative total protein, albumin, or creatinine is advisable. 12 In some patients, measurement of total protein is more useful than a measurement of albumin alone. For example, in children, total protein is useful to identify albuminuria and low-molecular weight proteinuria. 36 Measurement of total protein instead of albumin on a spot urine collection also is acceptable at high levels of proteinuria (spot urine total protein to creatinine ratio > mg/g). 36 proven simpler. Several of these equations have been validated and are widely used (Table 7). 12 Glomerular filtration rate can be estimated from equations that measure the serum creatinine concentration in the context of age, gender, race, and body size. In adults, the equations used are the Modification of Diet in Renal Disease (MDRD) study and Cockcroft-Gault equations (Table 7). 12 In children, the Schwartz and Counahan-Barratt equations are used. 12 K/DOQI guidelines recommend that clinical labora- Table 3. Correlation Between Spot Urine Albumin-to- Creatinine Ratio Versus Timed Urine Albumin in Adults Method of Correlation to Timed Study Year Patients, n Spot Urine Specimen (R 2 ) Zelmanovitz et al AM, not first (24 h) 0.85 Nathan et al Aliquots (24 h) 0.64 Ahn et al Random (24 h) 0.56 Ng et al AM (24 h) Sensitivity = 93%* Specificity = 94%* Ciavarella et al First AM (4 h) 0.96 Cottiero et al Unclear (4 h) 0.86 *Test threshold = 13.3 mg/l. Adapted with permission from National Kidney Foundation. Am J Kidney Dis. 2002;39:S1-S Table 4. Correlation Between Spot Urine Protein-to-Creatinine Ratio Versus Timed Urine Protein in Adults ESTIMATION OF GLOMERULAR FILTRATION RATE The best overall indices of the level of kidney function are estimates of the glomerular filtration rate (GFR). 12 Table 6 shows the correlation between GFR and the stages of chronic kidney disease. 12 Although GFR can be measured directly using inulin, the classic method for measuring inulin clearance requires an intravenous infusion and timed urine collections over a period of several hours. Therefore, GFR is costly and cumbersome. Several other alternative measures have been devised; however, predictive equations have Correlation Study Year Patients, n Method (R 2 ) Schwab et al Midday (24 h) 0.92 Ginsberg et al Random (24 h) 0.94 Rodby et al Random (24 h) 0.81* Zelmanovitz et al AM, not first (24 h) 0.52 Wilson and Anderson First AM (24 h) 0.83 Chu et al Aliquots (24 h) Steinhauslin and Wauters AM (24 h) 0.86 *After log/log transformation of data. Adapted with permission from National Kidney Foundation. Am J Kidney Dis. 2002;39:S1-S Advanced Studies in Medicine S23

5 tories report an estimate of GFR, in addition to the serum creatinine value. Although predictive equations are useful in estimating GFR in most patients, a 24-hour urine sample may provide more accurate information in those patients who deviate from the dietary norms, such as vegetarians and patients taking creatine supplements, and in those patients with changes in muscle mass resulting from events, such as amputation, malnutrition, and muscle wasting. The 24-hour urine sample also provides useful information for initiating dialysis treatment. 12 The accuracy of predictive equations is limited by extremes of age and body mass index, severe malnutrition or obesity, disease of skeletal muscle, paraplegia or quadriplegia, vegetarian diet, rapidly changing kidney function, and prior dosing of drugs with significant toxicity that are excreted renally. 12 K/DOQI, involved a systematic search for published data on diagnosis and management of the earlier stages of chronic kidney disease and was based on rigorous evidence. Although applicable to all types of kidney disease, the section in the guidelines on clinical assessment gives guidance on screening that is appropriate for patients with diabetes who may develop nephropathy. The ADA Clinical Practice Guidelines also aim to help clinicians better detect and diagnose nephropathy. The ADA Clinical Practice Guidelines are based on a review of the relevant literature by a diverse group of highly trained clinicians. After weighing the quality Table 5. Spot Urine Dipstick Albumin Versus Timed Urine Albumin in Adults MICROALBUMINURIA WITH CONCURRENT DIABETIC RETINOPATHY Some evidence suggests that the implication of microalbuminuria depends on the presence or absence of diabetic retinopathy. 37 In patients with type 2 diabetes mellitus, Parving et al found that most patients with proteinuria and with concurrent retinopathy had evidence of diabetic nephropathy, whereas only 60% of patients with proteinuria who did not have retinopathy had diabetic nephropathy. 37,38 More recently, a 5-year study suggests that patients with diabetes and its associated complications of retinopathy and microalbuminuria have a higher risk of progression to overt nephropathy compared to patients without retinopathy. 37 In patients with diabetes who do not have retinopathy, a clinical workup must be sufficient to assure other forms of renal disease are not present. Figure 2 shows an algorithm that is useful in primary care to evaluate kidney disease in patients with diabetes. PRACTICE GUIDELINES In 1999, the National Kidney Foundation (NKF) set out to develop practice guidelines to assist clinicians in providing better quality of care and outcomes for patients with early stage kidney disease. This initiative, known as the Method Study Year Patients, n of Spot Urine Sensitivity Specificity Webb et al Overnight 67%* 86%* Poulsen et al Random (24 h) 86% 97% Gerber et al Random (overnight) 75% 90% Random (24 h) 92% 63% *Test threshold = 20 mg/l; microalbuminuria 20 µg/min. Test threshold = 15 mg/l; microalbuminuria 30 mg/24 h (R 2 = 0.62). Test threshold = 20 mg/l; microalbuminuria 20 mg/l. Adapted with permission from National Kidney Foundation. Am J Kidney Dis. 2002;39:S1-S Table 6. Stages of Chronic Kidney Disease and Correlation to Glomerular Filtration Rate GFR Stage Description (ml min m -2 ) 1 Kidney damage with normal or GFR 90 2 Kidney damage with mild GFR Moderate GFR Severe GFR Kidney failure <15 (or dialysis) Chronic kidney disease is defined as kidney damage or GFR <60 ml min m -2 for 3 months. Kidney damage is defined as pathologic abnormalities of markers of damage, including abnormalities in blood or urine tests or imaging studies. GFR = glomerular filtration rate. Reprinted with permission from National Kidney Foundation. Am J Kidney Dis. 2002;39:S1-S S24 Vol. 5 (1A) January 2005

6 of evidence (ranging from rigorous double-blind clinical trials to expert opinion), recommendations are drafted, reviewed, and then submitted for approval to the ADA Executive Committee. These guidelines are revised on a regular basis and published. The NKF and the National Kidney Disease Education Program of the National Institutes of Health are developing new guidelines and implementing public health strategies that are complementary to the previous K/DOQI and ADA guidelines. These new guidelines are expected to be published between 2004 and PREDICTING PROGRESSION Another facet of screening and diagnosis of importance to the patient with diabetes is predicting diabetic nephropathy progression. Although there are many factors to consider, one that is clearly associated with progression is the urine albumin level. The higher the urine albumin level, the more likely the patient is to progress. Previously, small clinical trials had shown that improved glycemic control reduced the risk of progression of microalbuminuria ( mg/24 hours) to proteinuria (>300 mg/24 hours) in type 1 diabetes mellitus. 39,40 However, results from 2 additional clinical trials 41,42 were contradictory. Warram et al then performed a larger observational clinical trial to attempt to reconcile the evidence from these trials. 43 In this study, the investigators examined the doseresponse relationship between hyperglycemia and the progression of microalbuminuria to overt proteinuria in a study cohort of patients with type 1 diabetes mellitus and with microalbuminuria. Patients were observed for 4 years, and data for 279 subjects were analyzed. 43 In a comparison of the group of those patients who progressed to overt proteinuria and patients who did not, sex, age, duration of diabetes, and insulin dose were similar, in addition to the percentage of ideal body weight. Serum creatinine was similar for the 2 groups; however, the mean of the baseline determinations of the ratio of urinary concentrations of albumin and creatinine was found to be significantly higher in patients who progressed to proteinuria. 43 Therefore, the risk of progression to overt proteinuria was greatest for patients who were closest to microalbuminuria at baseline, as expected. The study projected the cumulative incidence of progression to be 34% to 47% after 10 to 15 years of observation, 43 which was Table 7. Equations to Predict Glomerular Filtration Rate Using Serum Creatinine Concentrations Adults Abbreviated MDRD Study Equation GFR = 186 [S Cr (mg/dl)] [Age(yrs)] (0.742 if female) (1.210 if African American) Cockcroft-Gault C Cr = [140 Age(yrs)] Weight(kg) (0.85 if female) 72 S Cr (mg/dl) Children Schwartz Equation Modified Counahan- Barratt Equation GFR = 43 Height(cm) S Cr (µmol/l) GFR = 40 Height(cm) S Cr (µmol/l) C Cr = creatinine clearance; GFR = glomerular filtration rate in mg ml m -2 ; MDRD = modification of diet in renal disease; S Cr = serum creatinine. Adapted with permission from National Kidney Foundation. Am J Kidney Dis. 2002;39:S1-S Figure 2. Evaluation of Kidney Disease in Patients with Diabetes Continue to screen at yearly intervals If abnormal urine sediment or GFR <60 ml/min, evaluate for other causes of kidney disease Screen for albuminuria Assess GFR & urinalysis NO YES YES NO Microalbuminuria mg/g creatinine Overt albuminuria >300 mg/g creatinine AND Diabetic nephropathy GFR normal or high ( 90 ml/min): CKD stage 1 GFR <90 ml/min: CKD stages 2 5 CKD = chronic kidney disease; GFR = glomerular filtration rate. Screen for retinopathy If evidence of kidney disease, evaluate for other causes Microalbuminuria or overt albuminuria GFR <60 ml/min Abnormal urinary sediment Advanced Studies in Medicine S25

7 quite different compared to previous findings. Before this study, researchers thought that 75% to 85% of patients with type 1 diabetes mellitus with microalbuminuria progressed to overt proteinuria during a 10- to 14-year period. 44,45 The study by Warram et al found that the risk of progression to overt proteinuria was significantly influenced by the level of glycemic control and the diastolic blood pressure rate. 43 The dose-response relationship for diastolic blood pressure was linear, but the dose-response relationship for glycemia was not. The risk of progression increases with increasing baseline hemoglobin A 1c (HbA 1c ) until it reaches approximately 8.5%. 43 At this level, the rise in risk is interrupted; at higher levels, the risk remains more or less constant. Warram et al concluded that based on this dose-response relationship, only patients whose glycemic control reduced their HbA 1c to less than 8.5%, and even more for those patients whose HbA 1c was close to 7.5%, may be expected to have a reduced risk of progression. 43 Gaede et al performed a controlled study (Steno-2 study) that included patients with type 2 diabetes mellitus who had microalbuminuria. 16 Some of the patients were randomly assigned to receive intensive treatment that included behavior modification and pharmacologic therapy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, in addition to aspirin therapy for secondary prevention of cardiovascular disease. The other patients received conventional treatment. The data showed patients receiving intensive therapy had a significantly lower risk of nephropathy (hazard ratio 0.39; 95% confidence interval). 16 Furthermore, the reduction in risk after 4 years of intensive intervention was maintained at 8 years. 16 These patients also had a reduced rate of cardiac events compared to the group receiving conventional therapy (24% vs 44%). 16 Measurement of GFR may also assist in predicting progression. An unusually high GFR in early onset diabetes mellitus may be another potential marker for progression; it can indicate underlying glomerular hyperfiltration and hypertension, although clinical studies have had difficulty confirming this, largely because of the long time course (>20 years) required for progression to occur. 45 Nevertheless, many patients with high GFRs at the time of diagnosis will experience GFR decline and, subsequently, renal failure. In experimental models, hyperfiltration has been shown to be a consequence of high pressure in the glomerular capillaries, even among patients with normal systemic blood pressure rates. These hemodynamic changes lead to eventual kidney damage. 46,47 CONCLUSIONS Diabetic nephropathy is a highly prevalent condition and is the most common cause of chronic kidney disease and renal failure in the United States and in developed countries. Based on the available evidence, our opportunities as clinicians to prevent cases of renal failure clearly are enhanced by early detection of diabetic nephropathy followed by the initiation of appropriate treatments. Therefore, the best approach is to understand the appropriate application for the various tests used to evaluate diabetic nephropathy, keeping in mind the available practice guidelines and the predictive value of progression. Earlier diagnosis will increase the opportunities for intervention with effective treatments, ultimately reducing the incidence of kidney disease in patients with diabetes. REFERENCES 1. Costa LA, Canani LH, Lisboa HR, et al. Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in type 2 diabetes. Diabet Med. 2004;21: Wong TY, Shankar A, Klein R, Klein BE. Retinal vessel diameters and the incidence of gross proteinuria and renal insufficiency in people with type 1 diabetes. Diabetes. 2004;53: Shah VO, Scavini M, Stidley CA, et al. Epidemic of diabetic and nondiabetic renal disease among the Zuni Indians: the Zuni Kidney Project. J Am Soc Nephrol. 2003;14: US Renal Data System (USRDS). USRDS 2003 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association. Diabetes and nephropathy (kidney complications). Available at: Accessed July 2, National Kidney Disease Education Program. Chronic kidney disease in the United States. Available at: sentation.pdf. Accessed June 28, Lemley KV. A basis for accelerated progression of diabetic nephropathy in Pima Indians. Kidney Int Suppl. 2003; 83:S38-S Molitch ME, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes. Diabetes Care. 2004;27:S79-S US Renal Data System (USRDS). USRDS 2000 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Rossert J, Fouqueray B. Screening and management of patients with early chronic kidney disease. Acta Diabetol. 2004;41:S6-S Joss N, Paterson KR, Deighan CJ, et al. Diabetic nephropathy: how effective is treatment in clinical practice? QJM. 2002;95: S26 Vol. 5 (1A) January 2005

8 12. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39:S1-S Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345: Hansen HP, Taubet-Lassen E, Jensen BR, Parving HH. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int. 2002;62: Perkins BA, Ficociello LH, Silva KH, et al. Regression of microalbuminuria in type 1 diabetes. N Engl J Med. 2003;348: Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348: ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med. 2001;134: Mogensen CE, Neldam S, Tikkanen I, et al. Randomized controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000;321: Warram JH, Gearin G, Laffel L, Krolewski AS. Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio. J Am Soc Nephrol. 1996;7: Zelmanovitz T, Gross JL, Oliveira JR, et al. The receiver operating characteristics curve in the evaluation of a random urine specimen as a screening test for diabetic nephropathy. Diabetes Care. 1997;20: Nathan DM, Rosenbaum C, Protasowicki VD. Single-void urine samples can be used to estimate quantitative microalbuminuria. Diabetes Care. 1987;10: Ahn CW, Song YD, Kim JH, et al. The validity of random urine specimen albumin measurement as a screening test for diabetic nephropathy. Yonsei Med J. 1999;40: Ng WY, Lui KF, Thai AC. Evaluation of a rapid screening test for microalbuminuria with a spot measurement of urine albumincreatinine ratio. Ann Acad Med Singapore. 2000;29: Ciavarella A, Silletti A, Forlani G, et al. A screening test for microalbuminuria in type 1 (insulin-dependent) diabetes. Diabetes Res Clin Pract. 1989;7: Cottiero RA, Madaio MP, Levey AS. Glomerular filtration rate and urinary albumin excretion rate in systemic lupus erythematosus. Nephron. 1995;69: Schwab SJ, Christensen RL, Dougherty K, Klahr S. Quantitation of proteinuria by the use of protein-to-creatinine ratios in single urine samples. Arch Intern Med. 1987;147: Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med. 1983;309: Rodby RA, Rohde RD, Sharon Z, et al. The urine protein to creatinine ratio as a predictor of 24-hour urine protein excretion in type 1 diabetic patients with nephropathy. Am J Kidney Dis. 1995;26: Zelmanovitz T, Gross JL, Oliveira J, de Azevedo MJ. Proteinuria is still useful for the screening and diagnosis of overt diabetic nephropathy. Diabetes Care. 1998;21: Wilson DM, Anderson RL. Protein-osmolality ratio for the quantitative assessment of proteinuria from a random urinalysis sample. Am J Clin Pathol. 1993;100: Chu NF, Ferng SH, Shieh SD, et al. Assessment of proteinuria by using the protein/creatinine ratio of single-voided urine. J Formos Med Assoc. 1990;89: Steinhauslin F, Wauters JP. Quantitation of proteinuria in kidney transplant patients: accuracy of the urinary protein/creatinine ratio. Clin Nephrol. 1995;43: Webb DJ, Newman DJ, Chaturvedi N, Fuller JH. The use of the Micral-Test strip to identify the presence of microalbuminuria in people with insulin dependent diabetes mellitus (IDDM) participating in the EUCLID study. Diabetes Res Clin Pract. 1996;31: Poulsen PL, Hansen B, Amby T, et al. Evaluation of a dipstick test for microalbuminuria in three different clinical settings, including the correlation with urinary albumin excretion rate. Diabetes Metab. 1992;18: Gerber LM, Johnston K, Alderman MH. Assessment of a new dipstick test in screening for microalbuminuria in patients with hypertension. Am J Hypertens. 1998;11: Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the National Kidney Foundation (NKF) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Am J Kidney Dis. 2003;42: Kim KS, Koh JM, Song KH, et al. Incidence of overt proteinuria and coronary artery disease in patients with type 2 diabetes mellitus: the role of microalbuminuria and retinopathy. Diabetes Res Clin Pract. 2004;65: Parving HH, Gall MA, Skott P, et al. Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int. 1992;41: Reichard P, Nilsson BY, Rosenqvist U. The effect of longterm intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993;329: The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329: Microalbuminuria Collaborative Study Group, United Kingdom. Intensive therapy and progression to clinical albuminuria in patients with insulin dependent diabetes mellitus and microalbuminuria. BMJ. 1995;311: The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 1995;47: Warram JH, Scott LJ, Hanna LS, et al. Progression of microalbuminuria to proteinuria in type 1 diabetes: nonlinear relationship with hyperglycemia. Diabetes. 2000;49: Viberti GC, Hill RD, Jarrett RJ, et al. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet. 1982;1: Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med. 1984;311: Zatz R, Meyer TW, Rennke HG, Brenner BM. Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A. 1985;82: Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982;307: Advanced Studies in Medicine S27