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Early Renal Disease:


Until recently, practitioners focused on the timing of initiation of renal replacement therapy (dialysis) and transplantation once advanced kidney disease had developed. However, a new CKD classification system now provides an action plan for the earlier stages of the disease.

Chronic kidney disease (CKD) has reached epidemic proportions in the United States. More than 6.2 million Americans have a serum creatinine level of 1.5 mg/dL or greater.1 Almost 20 million have some stage of CKD.2 Between 1987 and 1996, the incidence of end-stage renal disease (ESRD) doubled, and it continues to rise. Primary care clinicians are on the front lines of this epidemic.

Until recently, practitioners focused on the timing of initiation of renal replacement therapy (dialysis) and transplantation once advanced kidney disease had developed. However, a new CKD classification system now provides an action plan for the earlier stages of the disease.

In this article, we articulate an effective strategy for identifying renal disease in its early stages. We also describe interventions that can slow or prevent disease progression in patients with stage 1 or stage 2 CKD.


CKD is defined as a glomerular filtration rate (GFR) of less than 60 mL/min or structural/functional kidney abnormalities with a preserved GFR (90 mL/min or higher). In 2002, a National Kidney Foundation (NKF) work group defined 5 stages of CKD and delineated management goals for each stage (Table 1).3 Note that renal damage can occur in the absence of a decline in GFR. Thus, it is essential to be mindful of patients who are at risk for kidney disease.

Certain sociodemographic and clinical characteristics are associated with a higher risk of CKD (Table 2) and can be used to determine whether a patient is at risk for or has CKD. Screen patients who have no outstanding risk factors with blood pressure monitoring. If any CKD risk factors are present, obtain a thorough medical and family history and perform a review of systems. If the patient is at heightened risk for CKD, perform further evaluation based on risk assessment. For example, patients with diabetes or hypertension are at high risk for CKD and should be followed up every 6 to 12 months. Monitor biochemical markers of kidney disease, blood pressure, and estimated GFR in these patients. In addition, regularly examine urine to evaluate for proteinuria and/or hematuria.

GFR.This is the best measure of kidney function. Inulin clearance is the most accurate measure of GFR; however, it is an expensive and awkward test and is not practical for clinical use. Clinical laboratories do not routinely report GFR; instead, they report the serum creatinine concentration.

Unlike inulin, serum creatinine is not only filtered by the glomerulus but is also secreted by the proximal tubules. As renal function declines, the tubules increase creatinine secretion. This makes serum creatinine concentration a poor measure of GFR. In addition, the value is affected by a patient's muscle mass, diet, and medications––none of which are factored into the normal range for serum creatinine concentration that a laboratory provides. Therefore, it is important to assess "normal" values with caution and to interpret serum creatinine concentration in a patient-specific manner. For example, a 75-year-old Caucasian woman with a serum creatinine concentration of 1.5 mg/dL has a calculated GFR of 36 mL/min, while a healthy 25-year-old African American man with the same creatinine concentration has a calculated GFR of 73 mL/min.

To improve the usefulness of the serum creatinine concentration as a marker of kidney function, prediction equations were developed.4,5 To more accurately predict GFR, these formulas take into account a patient's race, age, gender, and body surface area, in addition to serum creatinine concentration. The 2 most commonly used formulas are shown in Table 3. The Cockcroft-Gault equation is easy to use but may represent a slight overestimation of GFR. The Modification of Diet in Renal Disease (MDRD) equation is more accurate; moreover, an easy-to-use, modified version of this equation has been developed.6 Currently, these equations are readily available on most personal digital assistant medical calculation programs or online. Neither formula should be used unless a patient's renal function is in steady state. Rapidly changing creatinine levels, such as are seen in acute renal failure, render these equations useless. However, the MDRD equation is frequently used to estimate GFR in many clinical settings.

Proteinuria. This is a key marker of kidney disease. Excessive proteinuria characteristically accompanies diseases of the glomerulus. Lower urinary protein concentrations are seen with tubulointerstitial, vascular, and cystic kidney disease.

An approach to the clinical evaluation of proteinuria is shown in the Algorithm. Urinary protein (or albumin):creatinine ratios are used because they correlate well with the results of 24-hour urine collections and are more convenient for patients. The algorithm is based on the NKF recommendation to use a different protocol for patients at risk for CKD than for those without risk factors.7

Asymptomatic patients who have no risk factors do not require routine screening for proteinuria. However, if proteinuria is detected by urine dipstick, evaluate it further. In patients with proteinuria, obtain a detailed family history and medication history, perform a physical examination, and order a urinalysis that includes evaluation of urinary sediment. Measurement of serum electrolytes, blood urea nitrogen level, glucose level, and estimated GFR are required to assess kidney function. For some patients, such as those in whom further studies or a kidney biopsy may be required for diagnosis, referral to a nephrologist is recommended.

In patients at risk for CKD (in particular, those with diabetes), routinely screen for albuminuria with an albumin-specific dipstick on a random spot urine sample (see Algorithm). Testing for microalbuminuria provides a more accurate measurement of proteinuria than use of a routine urinalysis dipstick. Routine dipsticks detect albuminuria only if the urinary albumin concentration is above 30 mg/dL.

Urinary sediment. In patients who have CKD or who are at high risk for kidney disease, evaluation of urinary sediment can provide a clue to the location of renal injury (Table 4). Cells seen in the urine may originate in the kidney or lower urinary tract. However, urinary casts form only in the kidney and can represent various types of cells, cellular debris, crystals, or fat or filtered proteins that are entrapped within Tamm-Horsfall protein (a high molecular weight glycoprotein) in the distal nephron.

Imaging studies. These play an important role in patients with established CKD and in those at high risk for kidney disease resulting from inherited polycystic kidney disease, urinary tract stones, obstruction, chronic infections, or vesicoureteral reflux disease. Ultrasonography is easy to perform and conveys significant diagnostic information. Table 5 outlines the clinical uses of this and other commonly used imaging studies.


Once early CKD has been diagnosed, aggressively pursue interventions to prevent progression of the disease. Especiallyin patients with diabetes or hypertension, early interventions can improve outcomes.

Glucose control. The landmark Diabetes Control and Complications Trial demonstrated that intensive glucose control impeded the development of microalbuminuria more effectively than conventional therapy in patients with type 1 diabetes.8 Intensive glucose control also benefits patients with type 2 diabetes by reducing microalbuminuria and proteinuria.9 Thus, it makes sense to optimize glycemic control in patients with diabetes, because this will likely slow the development of kidney disease. However, the benefits of lower blood glucose levels need to be weighed against the risk of hypoglycemia from extremely tight control. Thus, glucose goals should be individualized for each patient.

Blood pressure control. Hypertension increases the risk of progression of CKD. Blood pressure targets for various risk groups are shown in Table 6.

In patients who do not have diabetes. Nondiabetic kidney disease encompasses a large group of underlying renal diseases; some are characterized by proteinuria, while others are defined by functional or structural changes in the kidney. Strong evidence supports the importance of blood pressure control in slowing the progression of renal disease.3,10 Often, multiple agents are necessary.

To determine the best antihypertensive agent(s) for a particular patient, consider the following:

  • The etiology of his or her kidney disease.
  • Level of proteinuria.
  • Presence of comorbidities, such as cardiovascular disease.

Excessive intravascular volume is frequently a component of hypertension in patients with CKD. Therefore, diuretics are often effective in these patients. In the recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a subgroup of patients with kidney disease who did not have diabetes were shown to benefit from diuretics.11 The new NKF CKD blood pressure guidelines also recommend the use of diuretics.12 When used in combination with an angiotensin-converting enzyme (ACE) inhibitor, diuretics impede the development of hyperkalemia. In hypertensive patients without proteinuria, use an ACE inhibitor or angiotensin receptor blocker (ARB) in combination with a diuretic.

In patients with proteinuric kidney disease who do not have diabetes, ACE inhibitors and ARBs decrease proteinuria and slow the progression of CKD.13 Although calcium channel blockers are useful antihypertensive agents, in proteinuric renal disease, use them as second-line agents (after ACE inhibitors or ARBs).14

In patients with hypertension and early nondiabetic CKD, first assess the level of proteinuria.

  • If proteinuria is less than 200 mg/d, initiate a thiazide diuretic and, if needed, add an ACE inhibitor or ARB to reach goal blood pressure.
  • If proteinuria is greater than 200 mg/d, prescribe an ACE inhibitor or ARB as the first-line agent. If further blood pressure control is needed, add a thiazide diuretic.

If blood pressure is significantly elevated, prescribe a combination of ACE inhibitor or ARB plus a thiazide diuretic initially. If patients have significant proteinuria (more than 1 g/d), even if blood pressure is at goal, attempt to maximize the dose of the ACE inhibitor or ARB.

Reduction of proteinuria slows progression of CKD. There is good evidence to support the use of a dual blockade of the renin-angiotensin- aldosterone system (RAAS) with a combination of ACE inhibitor and ARB to further reduce proteinuria in patients with nondiabetic CKD.13 When ACE inhibitors and/or ARBs are used in patients with CKD, serum creatinine concentration often increases slightly. The increase is a result of hemodynamic changes in renal blood flow, and it reverses when the drug is stopped. Do not use such a finding to stop these agents prematurely. An increase of creatinine to 30% above baseline may be tolerated, presuming it stabilizes after 2 months.

In patients with diabetes. Like suboptimal glucose control, hypertension increases the risk of progression of diabetic kidney disease.15 The blood pressure goal is lower in patients with diabetic kidney disease (less than 125/75 mm Hg), regardless of their level of proteinuria.

The antihypertensive agents of choice in patients with diabetic kidney disease are ACE inhibitors and ARBs. Both drug classes reverse microalbuminuria. They also impede progression to microalbuminuria or proteinuria in patients with type 1 or type 2 diabetes who have normal levels of urinary albumin.3 We have found that even in patients with type 1 diabetes who are normotensive, interruption of the RAAS by an ACE inhibitor slows the progression of CKD.13

Several large, randomized, controlled trials have shown that in patients with type 2 diabetes and albuminuria, ARBs slow the decline of GFR and delay the onset of ESRD.14 Because most of the patients in these trials were also receiving a diuretic, we recommend adding a diuretic to RAAS blockade in this setting. However, combination therapy with an ACE inhibitor/ARB may be preferred to reach target blood pressure in patients with significant proteinuria. Adjust therapy to reduce the urinary protein level to less than 1 g/d.

Smoking cessation. Tobacco smoking may damage the kidney in several ways.16 Smoking induces a hyperfiltering state that may damage nephrons, as seen in diabetic nephropathy. Nephron injury may also result from hypertension caused or exacerbated by cigarette smoking. Aldosterone levels rise in smokers; the elevated levels may cause renal injury through both blood pressure and profibrotic effects. Smoking is an independent risk factor for albuminuria in men with hypertension and in patients with type 1 or type 2 diabetes.16 Thus, it is important to aggressively counsel patients that smoking worsens kidney disease and that cessation may slow progression to ESRD.17

Lipid control. Hyperlipidemia often complicates the course of CKD, even in the early stages. Several observational studies suggest that reducing elevated serum lipid levels may slow the progression of CKD. A well-done meta-analysis demonstrated a trend toward slowing of GFR decline in patients who were receiving statin therapy.17 Although no prospective, randomized, controlled trials of statin therapy have been performed, we recommend the aggressive use of cholesterol-lowering agents in patients with CKD.


Patients with CKD may benefit from evaluation by a nephrologist, who may be able to slow progression of renal failure and help in the management of comorbid conditions. When patients advance to stage 3 CKD, we suggest referral to a nephrologist.

CKD affects multiple organ systems, and patients need to be followed up closely as renal function deteriorates. Anemia develops, primarily from erythropoietin deficiency, and contributes significantly to cardiovascular morbidity. Bone disease results from secondary hyperparathyroidism and vitamin D deficiency. Frequently, chronic metabolic acidosis will develop and needs correction to improve nutritional status and bone health. Progressive azotemia also impairs quality of life and is associated with depression. A collaborative effort by the primary care provider and nephrologist improves CKD care.


REFERENCES:1. Coresh J, Wei GL, McQuillan G, et al. Prevalenceof high blood pressure and elevated serum creatininelevel in the United States: findings from thethird National Health and Nutrition ExaminationSurvey (1988-1994). Arch Intern Med. 2001;161:1207-1216.
2. Coresh J, Astor BC, Greene T, et al. Prevalenceof chronic kidney disease and decreased kidneyfunction in the adult US population: Third NationalHealth and Nutrition Examination Survey. Am J KidneyDis. 2003;41:1-12.
3. National Kidney Foundation Kidney DiseaseOutcomes Quality Initiative (K/DOQI) AdvisoryBoard. K/DOQI clinical practice guidelines forchronic kidney disease: evaluation, classification,and stratification. Kidney Disease Outcomes QualityInitiative. Am J Kidney Dis. 2002;39(suppl 1):S1-S290.
4. Cockcroft DW, Gault MH. Prediction of creatinineclearance from serum creatinine. Nephron.1976;16:31-41.
5. Levey AS, Bosch JP, Lewis JB, et al. A more accuratemethod to estimate glomerular filtration ratefrom serum creatinine: a new prediction equation.Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999;130:461-470.
6. Levey AS, Coresh J, Balk E. National KidneyFoundation practice guidelines for chronic kidneydisease: evaluation, classification, and stratification.Ann Intern Med. 2003;139:137-147.
7. Keane WF, Eknoyan G. Proteinuria, albuminuria,risk, assessment, detection, elimination (PARADE):a position paper of the National Kidney Foundation.Am J Kidney Dis. 1999;33:1004-1010.
8. The effect of intensive treatment of diabetes onthe development and progression of long-term complicationsin insulin-dependent diabetes mellitus.The Diabetes Control and Complications Trial ResearchGroup. N Engl J Med. 1993;329:977-986.
9. Intensive blood-glucose control with sulphonylureasor insulin compared with conventional treatmentand risk of complications in patients withtype 2 diabetes (UKPDS 33). UK Prospective DiabetesStudy (UKPDS) Group. Lancet. 1998;352:837-853.
10. Walker WG, Neaton JD, Cutler JA, et al. Renalfunction change in hypertensive members of theMultiple Risk Factor Intervention Trial. Racial andtreatment effects. The MRFIT Research Group.JAMA. 1992;268:3085-3091.
11. ALLHAT collaborative research group. Majoroutcomes in high-risk hypertensive patients randomizedto angiotensin-converting enzyme inhibitoror calcium channel blocker vs diuretic: the antihypertensiveand lipid-lowering treatment to preventheart attack trial (ALLHAT). JAMA. 2002;288:2981-2997.
12. Kidney Disease Outcomes Quality Initiative(K/DOQI). K/DOQI clinical practice guidelines onhypertension and antihypertensive agents in chronickidney disease. Am J Kidney Dis. 2004;43(suppl 1):S1-S290.
13. Brewster UC, Perazella MA. The renin-angiotensin-aldosterone system and the kidney: effects onkidney disease. Am J Med. 2004;116:263-272.
14. Wright JT Jr, Bakris G, Greene T, et al. Effectof blood pressure lowering and antihypertensivedrug class on progression of hypertensive kidneydisease: results from the AASK trial. JAMA. 2002;288:2421-2431.
15. Bakris GL, Williams M, Dworkin L, et al. Preservingrenal function in adults with hypertensionand diabetes: a consensus approach. National KidneyFoundation Hypertension and Diabetes ExecutiveCommittees Working Group. Am J Kidney Dis.2000;36:646-661.
16. Orth SR, Ritz E, Schrier RW. The renal risks ofsmoking. Kidney Int. 1997;51:1669-1677.
17. Fried LF, Orchard TJ, Kasiske BL. Effect oflipid reduction on the progression of renal disease:a meta-analysis. Kidney Int. 2001;59:260-269.

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