An eGFR of 30 classifies her as stage 4 CKD, with advanced renal disease. Her sCr alone would not accurately depict the severity of her kidney disease because of her dietary intake and lack of muscle mass. It is important to calculate eGFR every time you order sCr, while also closely observing your patient to determine whether his or her sCr accurately describes level of kidney function vs. muscle mass or dietary animal-protein intake.

The eGFR is not always accurate, however. As a general rule of thumb, consider an eGFR >60 as unreliable. In fact, many labs do not even report values >60. The eGFR is a product of the Modification of Diet in Renal Disease (MDRD) study. The patient population in the MDRD study had kidney disease (mean eGFR 39.4). This means that eGFR was not validated in patients without kidney disease. Since it was developed and validated in patients with moderate kidney disease, the formula cannot be used in patients with mild CKD (i.e., eGFR >60).


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Nevertheless, the eGFR is vital because it helps determine the stage of CKD (Table 2). Kidney disease is progressive, and many patients will move from stage 1 to stage 5 through the course of a lifetime.3 The time frame of progression is based on factors that can be influenced by treatments. The stage of CKD helps indicate when the patient will develop renal comorbidities attributable to kidney dysfunction.

Table 2. Stages of chronic kidney disease

Stage Description Estimated glomerular filtration rate (GFR)

1

Kidney damage with normal or elevated GFR

>90

2 Kidney damage with mild decrease in GFR 60-89

3

Moderate decrease in GFR

30-59

4 Severe decrease in GFR 15-29

5

Kidney failure

15

Source: Adapted from National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-S266.

The job functions of the kidneys include removal of toxins from the blood; acid/base regulation; BP control; fluid balance; maintenance of normal hemoglobin through production of erythropoietin; and regulation of vitamin D and the balance of minerals, including calcium, phosphorus, and potassium.

As the patient advances from stage 1 to stage 5 CKD, comorbid conditions will begin to develop due to the loss of the kidneys’ ability to perform various tasks. Patients in early stage 1 or 2 CKD may develop hypertension. In stages 2 and 3, bone and mineral abnormalities develop. Anemia related to CKD develops in stage 4, at which time patients will need aggressive management of these comorbid conditions. Most CKD patients should be referred to a nephrologist, who can work alongside the primary-care team to treat the disease and its comorbidities and slow the progression to ESRD.

Electronic medical records make it easy to graphically display trends of any lab value, and this is especially vital for the eGFR. With this in mind, plot the patient’s eGFR and/or sCr to view the trend of kidney function over a period of time. This visual will help illustrate to you whether the kidney disease is stable or progressing. Do not compare only one value to the previous value. Instead, look at all of the values over a period of time.

The first qualifier for decreased kidney function is an eGFR <60 for at least three months. The second qualifier is based on the presence of kidney damage. To determine whether a patient has kidney damage, look for albuminuria and/or other abnormal urinary sediment.

Clinical scenario 3: If Mr. H had a sCr of 0.9 mg/dL and eGFR >60 yet continued to have spot urine albumin/creatinine of 2,500 mg/g, he would still meet the criteria for CKD. Even with normal kidney function (eGFR  >60), he has the presence of kidney damage based on his level of albuminuria or proteinuria. This can be seen early on in the development of diabetic nephropathy.

Renal function can be normal, but the presence of micro­albuminuria (30-300 mg/g) would demonstrate that kidney damage is occurring even though it has not yet resulted in a decline in kidney function. An albumin/creatinine ratio >30 mg/g for at least three months is an indication of CKD. Because there are different types of urinary protein, the term albuminuria is used interchangeably with proteinuria. However, urine albumin makes up the majority of urinary protein.

The three ways of evaluating the presence of proteinuria are by urine dipstick, 24-hour urine collection, and spot urine albumin/creatinine. Urine dipstick is a relatively crude quantification of urinary albumin and does not accurately determine the presence of microalbuminuria. Additionally, urine dipstick does not detect urinary protein other than albumin and can be affected by the overall state of urine concentration or dilution.4

A 24-hour urine collection allows the clinician to determine the level of protein excreted in the patient’s urine over a 24-hour period, total salt consumption, and creatinine clearance (CrCl). The CrCl and eGFR are both used to determine renal function: The CrCl determines renal function based on results from a 24-hour urine collection, and the eGFR calculates renal function from a blood collection (as described above).

However the CrCl is not the most accurate method for determining kidney function.5 The accuracy of any 24-hour urine collection to determine an individual’s level of proteinuria, daily salt consumption, or level of kidney function depends on adherence to proper collection. Therefore, the results are susceptible to inaccuracy caused by over- or under-collection. If the patient collected for only 20 hours, then the CrCl, level of proteinuria, and salt consumption would be underestimated.

A proper 24-hour urine collection can be challenging. The patient must not miss a collection. The urine specimen must also be kept on ice for the entire 24-hour period. Although not always inaccurate, the 24-hour urine collection is not the preferred method for routine screening for proteinuria.

A random or spot urine sample is the preferred method of screening for proteinuria, especially microalbuminuria, which is the only early clue to the development of kidney disease in patients with diabetes.6 Order a spot urine albumin and creatinine and calculate the ratio of urinary albumin to urinary creatinine. The result is expressed in mg/g and will approximate the amount of albumin excreted into the urine in a 24-hour period. The urine albumin-to-creatinine ratio corrects for the amount of dietary creatinine intake and standardizes the collection. Table 3 depicts an algorithm to follow when screening for proteinuria.

Table 3. Evaluation of proteinuria

Download PDF – Table 3. Evaluation of proteinuria

Vigorous exercise or infections can result in transient proteinuria, so testing must be repeated within three months.

Step 3: Treatment of CKD

After determining the level of kidney function (based on eGFR) and/or the presence of kidney damage (based on albuminuria) and staging the level of CKD, it is time to start treatment. As previously discussed, CKD is progressive, and most patients will advance to kidney failure, ESRD, and eventually death. CKD also puts patients at increased risk for developing cardiovascular events independent of medical history.6

Clinical scenario 4: What if Mr. H did not have hypertension, CVD, or diabetes? What if he was not a smoker? If Mr. H only had CKD, would he be at risk for developing CVD? The answer is, “yes.”

A 2004 study investigated the rate of cardiovascular events, hospitalization, and death in patients who had CKD.6 Prior to this study, the data showed that patients with ESRD had mortality rates higher than 20% per year with the use of dialysis, and more than half of these deaths were related to CVD.

The study followed approximately 1.1 million adults in whom sCr had been measured and who had not undergone dialysis or kidney transplantation. Median follow-up was 2.84 years, mean age was 52 years, and 55% of the participants were women. The cohort was examined for a multivariable association between the eGFR and the risks of death, cardiovascular events, and hospitalization. The results were astonishing:

  • A reduced eGFR was associated with increased risks of death, cardiovascular events, and hospitalization, independent of such known risk factors as history of CVD or proteinuria.
  • Risk of death from any cause increased sharply as the eGFR declined—from a 17% increase in risk with an eGFR of 45-49 to a nearly 600% increase with an eGFR of <15.
  • Risk of cardiovascular events increased as the eGFR declined—from a 43% increase in risk with an eGFR of 45-49 to a 343% increase with an eGFR of <15.
  • Risk of hospitalization increased as the eGFR declined—from a 14% increase in risk with an eGFR of 45-49 to a 315% increase with an eGFR of <15.

These findings highlight the clinical and public-health importance of CKD. As early as stage 3 CKD (eGFR 45-49), patients are at increased risk of developing cardiovascular events independent of medical history.

The goals of CKD treatment are to slow the progression to ESRD and decrease risk of cardiovascular events. Halting the disease progression is based on two treatment modalities: (1) lowering BP to <130/80 mm Hg; and (2) inhibiting the renin-angiotensin-aldosterone system (RAAS) and to limit proteinuria.

Current guidelines recommend a BP target of <130/80 to treat all types of kidney disease and to reduce cardiovascular risk.2 BP control can make a significant difference in the rate of kidney decline. Controlling BP is the single most important factor in slowing the progression of CKD and is the most predictive value for determining time to ESRD.

For example, Mr. H has a BP of 150/100 and will progress to ESRD in five years. Lowering his BP to <130/80 will lengthen his time to ESRD to 20 years.

As most clinicians know from experience, reducing BP is not easy, especially if the patient is not motivated, which is where patient education comes in.

Step 4: Education, education, and more education

Educating individuals with CKD regarding their role in the treatment of the disease is essential. Each patient must understand the importance of BP control in preserving his or her remaining level of kidney function.

Begin by explaining that the BP goal is <130/80. Second, emphasize that if the BP goal is not met, progression to ESRD will occur at a more rapid rate. Third, encourage consistent home BP monitoring, which is more accurate than intermittent office readings.

Each CKD patient should be taught to accurately monitor and record BP daily (Table 4). These BP readings should be brought to every clinic visit. Finally, discuss treatment options, including medications and such lifestyle changes as low-sodium diet (<2,000 mg/day), modest weight loss, smoking cessation, limiting alcohol, and exercise. Explain that multiple therapeutic agents will be necessary to reach the BP goal.7

Table 4. Accurate BP monitoring

Measure twice daily (am and pm) for one week. Before measuring, sit for five minutes with the arm at the height of the heart.
If no difference between AM and PM is noted, measure daily. Sit with the legs uncrossed.
Measure at the same time every day. An arm cuff is more accurate than a wrist cuff.
Use the same arm for each measurement. Home measurement is more accurate than office measurement.

ACE inhibitors or angiotensin-receptor blockers (ARBs) are indicated for individuals who have diabetes with or without hypertension and for CKD patients with proteinuria (Table 5).7 In patients with CKD with proteinuria (>200 mg/g), inhibition of the RAAS axis is superior to conventional antihypertensive drug therapy in slowing the decline of renal function.8

If a CKD patient does not have diabetes or proteinuria, a thiazide diuretic would be indicated as first-line therapy. ACE inhibitors/ARBs should be used at moderate to high doses, and patients should be monitored carefully for hypotension, decrease in eGFR, and hyperkalemia.2

Clinical scenario 5: Mr. H has a BP of 150/100 and a heart rate of 89 beats per minute while on metoprolol and HCTZ. His urine albumin/creatinine is 2,500 mg/g. What medication changes would be needed to achieve optimal BP (i.e., <130/80)?

  1. Start ACE inhibitor or ARB.
  2. Discontinue HCTZ and start furosemide (Lasix).
  3. Increase metoprolol based on heart rate.
  4. All of the above

The answer is “all of the above.” An individual with diabetes and proteinuria needs an ACE inhibitor/ARB. HCTZ is not an effective diuretic once eGFR is <50. Loop diuretics help mitigate the hyperkalemia commonly seen in CKD patients taking ACE inhibitors/ARBs. Another treatment option would be to up-titrate metoprolol based on heart rate.

Table 5. BP-lowering medications

Type of kidney disease BP target (mm Hg) Recommended agents for CKD with or without hypertension Other agents to reduce CV risk and reach BP target

Diabetic

<130/80

ACE inhibitor or angiotensin-­receptor blocker (ARB)

Diuretics preferred, followed by beta blocker (BB) or calcium channel blocker (CCB)

Nondiabetic with proteinuria <130/80 ACE inhibitor Diuretics preferred, followed by BB or CCB

Nondiabetic without proteinuria

<130/80

No preference

Diuretics preferred, followed by ACE inhibitor, ARB, BB, or CCB

Mr. H is already on two agents, and the BP is suboptimal. Most CKD patients will require at least two and as many as five antihypertensive medications. Educate patients to know which BP-lowering medications they are taking and stress the importance of taking the medications at the same time every day.

Consistency is the key. Encourage medication compliance by prescribing once-daily dosing or combination drugs whenever possible. Education will motivate patients and must be a component of every office visit. Increase emphasis on education when BP-lowering strategies are unsuccessful.

The next component of treating CKD is to limit the amount of proteinuria through inhibition of RAAS. RAAS inhibition provides nephroprotection independent of BP lowering and is mainly achieved through the use of ACE inhibitors and ARBs. Higher levels of proteinuria are associated with faster progression of CKD and increased risk of CVD.2,9-12

Decline in the eGFR varies by disease state from patient to patient but is accelerated in individuals with proteinuria. Focal segmental glomerulosclerosis (FSGS) is a glomerulopathy that can lead to nephrotic-range proteinuria (>3.0 g of proteinuria in 24 hours). Diabetic nephropathy can lead to microalbuminuria (30-300 mg), followed by macroalbuminuria (>300 mg), and then on to nephrotic ranges.

Autosomal dominant polycystic kidney disease (ADPKD) does not lead to significant proteinuria. FSGS progresses to ESRD at a much more rapid rate compared with diabetic nephropathy, and diabetic nephropathy progresses to ESRD at a more rapid rate compared with ADPKD. It is thought that the different rates of progression to ESRD are partially attributable to the amount of proteinuria.10-12

Among patients with CKD, proteinuria is an important and independent risk factor for CVD and mortality.9 Treating proteinuria with medications that hinder the RAAS blockade slow progression to ESRD and limit cardiovascular events.9,12

Conclusion

Primary-care clinicians must screen all individuals who are at risk for CKD and then aggressively treat with multiple antihypertensive agents BPs that are not at goal of <130/80. Initiate RAAS-blockade agents in CKD patients who are diabetic or have proteinuria. Refer early to nephrology for education on transplant or dialysis and for treatment of the associated comorbidities (e.g., anemia of CKD, bone/mineral disorder, electrolyte abnormalities, and fluid balance).

Denise Keller Link, MPAS, PA-C, is a nephrology physician assistant at The University of Texas Southwestern Medical School in Dallas.

References

  1. U.S. Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2012.
  2. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-S266.
  3. Jaber BL, Madias NE. Progression of chronic kidney disease: can it be prevented or arrested? Am J Med. 2005;118:1323-1330.
  4. Jayne AD. Hematuria and proteinuria. In: Greenburg A. Primer on Kidney Diseases: Expert Consult, 5th ed. Philadelphia, Pa.: Saunders Elsevier; 2009:33-42.
  5. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305.
  6. National Heart, Lung, and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
  7. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456-1462.
  8. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.
  9. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123:754-762.
  10. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019-2032.
  11. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421-2431.

All electronic documents accessed January 15, 2013.