Detection and evaluation of chronic kidney disease

Author: Susan Snyder, Bernadette Pendergraph
Date: Nov 1, 2005

Chronic kidney disease affects approximately 19 million adult Americans, and its incidence is increasing rapidly. Diabetes and hypertension are the underlying causes in most cases of chronic kidney disease. Evidence suggests that progression to kidney failure can be delayed or prevented by controlling blood sugar levels and blood pressure and by treating proteinuria. Unfortunately, chronic kidney disease often is overlooked in its earliest, most treatable stages. Guidelines from the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) recommend estimating glomerular filtration rate and screening for albuminuria in patients with risk factors for chronic kidney disease, including diabetes, hypertension, systemic illnesses, age greater than 60 years, and family history of chronic kidney disease. The glomerular filtration rate, calculated by using a prediction equation, detects chronic kidney disease more accurately than does the serum creatinine level alone; the glomerular filtration rate also is used for disease staging. In most clinical situations, analysis of random urine samples to determine the albumin-creatinine or protein-creatinine ratio has replaced analysis of timed urine collections. When chronic kidney disease is detected, an attempt should be made to identify and treat the specific underlying condition(s). The KDOQI guidelines define major treatment goals for all patients with chronic kidney disease. These goals include slowing disease progression, detecting and treating complications, and managing cardiovascular risk factors. Primary care physicians have an important role in detecting chronic kidney disease early, in instituting measures to slow disease progression, and in providing timely referral to a nephrologist.

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Approximately 19 million Americans older than 20 years have chronic kidney disease, and an additional 435,000 have end-stage renal disease (Table 1 (1)). The incidence of end-stage renal disease, with its annual mortality rate of 24 percent, has doubled every decade since 1980. (2) Chronic kidney disease is 100 times more prevalent than end-stage renal disease, and its incidence is increasing at an even faster rate.

Early treatment of chronic kidney disease and its complications may delay or prevent the development of end-stage renal disease. Consequently, detection of chronic kidney disease should be a priority for family physicians. However, data from national screening programs suggest that chronic kidney disease often is not detected, even when patients have access to primary care. (3,4)

The Kidney Disease Outcomes Quality Initiative (KDOQI) from the National Kidney Foundation (NKF) has developed guidelines for the detection and evaluation of chronic kidney disease. (5,6) These guidelines define the disease and its stages and outline treatment goals for each stage. This article focuses on the detection of chronic kidney disease and the initial evaluation of affected patients.

Detection of Chronic Kidney Disease

WHICH PATIENTS TO SCREEN

The KDOQI guidelines (1,6) recommend assessing all patients for kidney-disease risk factors. Further screening is performed in patients with identified risk factors. Although screening methods for chronic kidney disease have not been evaluated in randomized controlled trials, (7) the high prevalence of the disease in at-risk populations, the ease of screening, and the availability of effective treatments during early asymptomatic stages of the disease provide sufficient rationale for screening. (8) Nonetheless, screening rates for patients with known risk factors for chronic kidney disease are as low as 20 percent. (3,4)

High-risk groups that should be screened for chronic kidney disease include patients who have a family history of the disease and patients who have diabetes, hypertension, recurrent urinary tract infections, urinary obstruction, or a systemic illness that affects the kidneys. (1) A recent analysis (9) suggested that screening all patients older than 60 years is cost-effective even when other risk factors for chronic kidney disease are absent; screening low-risk patients younger than 60 years does not appear to be cost-effective.

Diabetes is the most common cause of kidney disease. From 40 to 60 percent of patients who progress to end-stage renal disease have diabetes. Other underlying conditions in patients with end-stage renal disease include hypertension (15 to 30 percent), glomerulonephritis (less than 10 percent), and cystic kidney (2 to 3 percent). Unknown causes account for the remaining patients with end-stage renal disease. (2)

HOW TO SCREEN

Screening patients at risk for chronic kidney disease relies on the detection of functional abnormalities using readily available, inexpensive laboratory tests. The measured serum creatinine level is used to calculate an estimated glomerular filtration rate (GFR). Screening for proteinuria often alerts the physician to the presence of chronic kidney disease before changes in the GFR become apparent.

Current KDOQI guidelines (1,5,6) recommend screening for kidney disease with a serum creatinine measurement for use in GFR estimation and analysis of a random urine sample for albuminuria. Significant kidney disease can present with decreased GFR or proteinuria, or both. An analysis (7) of data from the third National Health and Nutrition Examination Survey (NHANES III) showed that 20 percent of persons with diabetes, and 43 percent of persons with hypertension and a GFR below 30 mL per minute per 1.73 [m.sup.2], had no proteinuria. Therefore, an estimate of the GFR and a screening method for proteinuria are required. (1)

Selected patients with risk factors for kidney disease should be screened with renal ultrasonography. Indications for this study include suspected urinary tract obstruction, recurrent urinary tract infections, vesicoureteral reflux, and a family history of polycystic kidney disease. (1)

ESTIMATING THE GFR

The GFR is an indication of functioning kidney mass; it has implications for treatment goals and for the dosing of renally excreted medications. (10) The KDOQI guidelines define stages of chronic kidney disease based on an estimated GFR that is calculated from the serum creatinine level (Table 2 (1)).

The standard for GFR measurement is the clearance rate of inulin, a substance that passes through the kidney unchanged. Creatinine clearance, as measured by a 24-hour urine collection, usually overestimates the GFR because of the active secretion of creatinine by the kidney and can vary with muscle mass. (11)

Significant kidney dysfunction may be present despite a normal serum creatinine level. An estimation of the GFR based on the serum creatinine level correlates better with direct measures of the GFR and detects more cases of chronic kidney disease than does the serum creatinine level alone. Furthermore, patients with the same serum creatinine level may have different estimated GFRs. For example, a 45-year-old black man whose serum creatinine level is 1 mg per dL (88 [micro]mol per L) has normal kidney function with an estimated GFR of 130 mL per minute per 1.73 [m.sup.2], whereas a 65-year-old white woman with the same serum creatinine level has an estimated GFR of 59 mL per minute per 1.73 [m.sup.2], or stage 3 kidney disease.

Based on an analysis (7) of NHANES III data, 20 percent of persons with diabetes, and 14.2 percent of persons with hypertension but no diabetes, have a GFR below 60 mL per minute per 1.73 [m.sup.2]. The prevalence of GFRs below 60 mL per minute per 1.73 [m.sup.2] increases steadily with age; 22.5 percent of nondiabetic, nonhypertensive octogenarians have a GFR below this level.

Clinically useful GFR estimates are calculated from the measured serum creatinine level (12,13) after adjustments for age, sex, and race. A GFR of 100 mL per minute per 1.73 [m.sup.2] is considered normal for women, and 120 mL per minute per 1.73 [m.sup.2] is a normal GFR for men. (1) The two most commonly used formulas for GFR estimation are shown in Table 3. (12-18) These methods have been studied in a variety of populations. 12,14-18 Validation studies (12) performed in middle-aged patients with chronic kidney disease showed that the Modification of Diet in Renal Disease (MDRD) study equation was more accurate than the Cockcroft- Gault equation, which calculates creatinine clearance. In a recent study, (18) however, the MDRD study equation was found to systematically underestimate the GFR in patients without chronic kidney disease.

SORT: KEY RECOMMENDATIONS EvidenceClinical recommendation rating ReferencesAll adults with risk factors for chronic C 1, 5, 6kidney disease should be screened with a serumcreatinine determination for GFR estimationand analysis of a random urine sample forproteinuria.Instead of a timed urine collection, a random C 1, 24, 25urine sample for the microalbumin-creatinineor protein-creatinine ratio should be used toquantify proteinuria.Interventions proved to slow the progression A 1, 24, 33,of chronic kidney disease include bloodpressure control, glycemic control, and 34, 37reduction of proteinuria with an angiotensin-converting enzyme inhibitor or angiotensin-IIreceptor blocker.A low-density lipoprotein goal of less than C 37100 mg per dL (2.60 mmol per L) is recommendedfor patients with chronic kidney disease,because these patients are statistically athighest risk for cardiovascular disease.A blood pressure goal of 130/80 mm Hg is B 1, 30recommended in patients with normal urinaryalbumin concentrations, and a blood pressuregoal of 125/75 mm Hg is recommended inpatients with proteinuria equal to or greaterthan 1 g per 24 hours.GFR = glomerular filtration rate.A = consistent, good-quality patient-oriented evidence;B = inconsistent or limited-quality patient-oriented evidence;C = consensus, diseaseoriented evidence, usual practice, expertopinion, or case series. For information about the SORT evidencerating system, see page 1639 or http://www.aafp.org/afpsort.xml.TABLE 1Definitions from the national Kidney Foundation'sKidney Disease outcomes Quality initiativeChronic kidney diseaseKidney damage for three or more months based on findings of abnormal structure (imaging studies) or abnormal function (blood tests, urinalysis) orGFR below 60 mL per minute per 1.73 [m.sup.2] for three or more months with or without evidence of kidney damageEnd-stage renal disease (kidney failure)GFR below 15 mL per minute per 1.73 [m.sup.2] orNeed for kidney replacement therapy (dialysis or transplant)GFR = glomerular filtration rate.Adapted with permission from National Kidney Foundation. K/DOQI,clinical practice guidelines for chronic kidney disease: evaluation,classification, and stratification. Am J Kidney Dis2002;39(2 suppl 1):S1-266. Accessed online February 15, 2005, at:http://www.kidney.org/professionals/kdoqi/guidelines_ckd/GIF_File/kck_t2.gif.TABLE 2Stages of Chronic Kidney DiseaseBased on estimated GFR GFR (mL per minuteStage per 1.73 [m.sup.2])1 [greater than or equal to] 902 60 to 893 30 to 594 15 to 295 < 15 or dialysisGFR = glomerular filtration rate.Information from reference 1.TABLE 3Formulas for estimating GFR in adults *Abbreviated MDRD study equation (12) ([dagger])GFR (mL per minute per 1.73 [m.sup.2]) =186 x [([S.sub.Cr]).sup.-1.154] x [(age).sup.-0.203] x (0.742, if female) x (1.210, if black)Cockcroft-Gault equation (13)[C.sub.Cr] (mL per minute) = (140 - age) x weight/72 x [S.sub.Cr]x (0.85, if female)GFR = glomerular filtration rate; MDRD = Modification of Diet in RenalDisease; [S.sub.Cr] = serum creatinine concentration; [C.sub.Cr] =creatinine clearance.*--For each equation, [S.sub.Cr] is in milligrams per deciliter, age isin years, and weight is in kilograms.([dagger])--In validation studies, (14-17) the MDRD study equationperformed as well as versions with more variables; however, a recentstudy (18) found that the equation underestimated the GFR in patientswho did not have chronic kidney disease.Information from references 12 through 18.TABLE 4Preferred Methods for Assessing Kidney FunctionMethod Situations for useMDRD study equation Patients with diabetic kidney disease for estimating GFR * ([dagger]) Patients with chronic kidney disease in middle-age (average age: 51 years) ([dagger]) Black patients with hypertensive chronic kidney disease ([dagger]) Patients with a kidney transplant ([dagger])Cockcroft-Gault equation Older patients (performs better than the for estimating creatinine MDRD study equation) clearance *24-hour urine collection Pregnant women for creatinine clearance Patients with extremes of age and weight Patients with malnutrition Patients with skeletal muscle diseases Patients with paraplegia or quadriplegia Patients with a vegetarian diet and rapidly changing kidney functionMDRD = Modification of Diet in Renal Disease;GFR = glomerular filtration rate.*--Requires stable kidney function.([dagger])--Validated for use in these patients.Based on information from references 3 and 12 through 17.TABLE 5Diagnostic evaluation in Chronic Kidney DiseaseDisorder Clinical clues Urine sedimentDiabetes mellitus Diabetes for > 15 years, RBCs in < 25 retinopathy percent of affected patientsEssential Left ventricular Benign hypertension hypertrophy, retinopathyGlomerulonephritis History and physical Dysmorphic examination: RBCs or RBC infections; rash, casts arthritis; patient older than 40 yearsInterstitial Medications, fever, WBCs, WBC nephritis rash, eosinophilia casts, eosinophilsLow flow states Volume depletion, Hyaline casts, hypotension, eosinophils congestive heart failure, cirrhosis, atherosclerosisUrinary tract Urinary symptoms Benign, or RBCs obstructionChronic urinary Urinary symptoms WBCs, RBCs tract infectionNeoplasm, Patient older than RBCs, RBC casts, paraproteinemia 40 years, constitutional granular casts symptoms, anemiaCystic kidney Palpable kidneys with RBCs disease or without family history of cystic kidney disease, flank painRenovascular Late-onset or refractory Benign disease hypertension, sudden onset of hypertension in young woman, smoking history, abdominal bruitVasculitis Constitutional RBCs; granular symptoms, peripheral casts neuropathy, rash, respiratory symptoms Protein-creatinineDisorder ratio Additional testsDiabetes mellitus > 30 to > 3,500 mg Fasting blood sugar, A1C of protein per g of creatinineEssential > 30 to 3,000 mg No additional tests hypertension of protein per gram of creatinineGlomerulonephritis > 30 to > 3,500 mg C3 and C4 for all of protein per g patients of creatinine Tests for infections: anti-ASO, ASK, HIV, HBsAg, HCV, RPR, blood cultures Tests if there is rash or arthritis: ANA, ANCA, cryoglobulin, anti-GBM Tests if patient is older than 40 years: SPEP, UPEPInterstitial 30 to 3,000 mg ACE level; SS-A, SS-B nephritis of protein per g of creatinineLow flow states < 200 mg of protein FENa: < 1 percent; per g of creatinine eosinophiliaUrinary tract None KUB radiography, obstruction intravenous pyelography, spiral CT scanning, renal ultrasonographyChronic urinary < 2,000 mg of protein Pelvic examination, tract infection per g of creatinine urine culture, voiding cystourethrography, renal ultrasonography, CT scanningNeoplasm, False-negative result SPEP, UPEP, calcium paraproteinemia or > 30 to > 3,500 level, ESR mg of protein per g of creatinineCystic kidney 30 to 3,000 mg of Renal ultrasonography or disease protein per g of CT scanning if there is creatinine a complex kidney cyst or massRenovascular < 200 mg of protein Renal Doppler disease per g of creatinine ultrasonography, radioisotope renal scanning, MRA, renal angiographyVasculitis > 30 to > 3,500 mg C3, C4, ANA, ANCA; HBsAg, of protein per g of HCV, cryoglobulins, creatinine ESR, RF, SS-A, SS-B, HIVRBC = red blood cell; A1C = glycosylated hemoglobin; C3 = complement3; C4 = complement 4; anti-ASO = steptolysin O latex antibody;ASK = antistreptokinase; HIV = human immunodeficiency virus;HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus;RPR = rapid plasma reagin; ANA = antinuclear antibodies;ANCA = antineutrophil cytoplasmic antibody; anti-GBM = anti-glomerularbasement membrane antibody; SPEP = serum protein electrophoresis;UPEP = urine protein electrophoresis; WBC = white blood cell;ACE = angiotensin-converting enzyme; SS-A = anti-Ro antibody;SS-B = anti-La antibody; FENa = fractional excretion of sodium;KUB = kidney, ureters, and bladder; CT = computed tomography;ESR = erythrocyte sedimentation rate; MRA = magnetic resonanceangiography; RF = rheumatoid factor.Adapted from Chronic kidney disease and pre-ESRD. Management inthe primary care setting. Accessed February 24, 2005, at:http://www.oqp.med.va.gov/cpg/ESRD/ESRD_cpg/app/bot_app_1.htm.Table 6Imaging options in Chronic Kidney DiseaseImaging study What the study helps identifyPlain-film radiography of Ureter or bladder stoneskidneys, ureters, and bladderRenal ultrasonography Kidney size, obstructive kidney disease, polycystic kidney diseaseRenal Doppler Renovascular disease, renal veinultrasonography thrombosisRadioisotope renal scanning Individual kidney function, renovascular disease, obstructive uropathyComputed tomography Kidney mass or complex cystMagnetic resonance Renovascular diseaseangiographyRenal angiography Renovascular disease, renal artery thrombosis/thromboembolism, polyarteritis nodosaRetrograde ureterography Upper urinary tract obstructionNOTE: Intravenous pyelography generally is not performed in patientswith chronic kidney disease because it may precipitate acute renalfailure. Information from references 1 and 28.Table 7screening for Complications in Chronic Kidney Disease(stages 3 and 4 *)Test Complications detectedHemoglobin concentration AnemiaRed blood cell indexes, For ruling out other causes ofreticulocyte count, iron anemia before erythropoietin therapystudies, fecal occult blood test is startedSerum electrolyte levels Hyperkalemia, hyponatremia, acidosisCalcium, phosphorus, and Hypocalcemia, hyperphosphatemia,parathyroid hormone levels secondary hyperparathyroidismSerum albumin and total Hypoalbuminemia, decreased levelsprotein levels of immunoglobulins in patients with nephritic levels of proteinuria or signs of malnutrition*--Patients with a glomerular filtration rate below 60 mL per minuteper 1.73 [m.sup.2]. Information from references 1 and 28.TABLE 8Indications for nephrology referralin Chronic Kidney DiseaseUnderlying cause unclear after basic work-upRenal biopsy indicatedManagement of underlying cause beyond the scope of primary careStage 3 chronic kidney disease (GFR < 60 mL per minute per 1.73[m.sup.2]): consider comanagementStage 4 chronic kidney disease (GFR < 30 mL per minute per 1.73[m.sup.2]): nephrologist involvement essentialRapid progression of chronic kidney diseaseSuperimposed acute kidney failureGFR = glomerular filtration rate.Information from references 6, 11, 28, 38, and 40.

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