Course Authors
Devraj Munikrishnappa, M.D.
Dr. Munikrishnappa is Adjunct Clinical Instructor, Department of Geriatrics, Saint Louis University School of Medicine, St. Louis, Missouri.
Within the past 12 months, Dr. Munikrishnappa reports no commercial conflicts of interest.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe the currently widely recommended method of assessing kidney function
Discuss the National Kidney Foundation (NKF) recommended definition and stages of CKD
Discuss the outlines of NKF-recommended action plans for each stage of CKD.
Chronic kidney disease (CKD) affects about 20 million American adults. The incidence in the elderly is rising disproportionately. Nearly 25% of the U.S. elderly population who were non-institutionalized and aged 70 years or older were found to have CKD.(1),(2),(3) It is, however, not surprising that the elderly are predisposed to developing CKD, considering the number of comorbid diseases and conditions associated with aging such as diabetes and hypertension that also affect the kidney. Indeed, age itself is an independent risk factor for renal disease, particularly for proteinuria (a marker of renal dysfunction), and this was reconfirmed by Yamagata and colleagues in their recent 10-year follow-up study.(4) Besides, an aging kidney has less capacity to cope with stressful challenges owing to its anatomical and functional changes.
Assessing Kidney Function
Kidney function is best reflected by glomerular filtration rate (GFR). It can practically be assessed in more than one way, for example, estimation equations from serum creatinine or creatinine clearance measurement by 24-hour urine collection. More recently, literature has been accumulating on serum cystatin C as a marker of renal function. The gold standard of measurement of GFR, of course, is by direct measurement of inulin clearance.
The estimation of kidney function by serum creatinine alone has numerous limitations, particularly in the elderly, as it is affected by age, sex, muscle mass, diet and medications. Because of these factors, in certain situations, serum creatinine may not accurately reflect GFR despite a decrease in GFR to <60 ml per minute per 1.73 m2.(5) Nevertheless, serum creatinine can be used to monitor kidney function in those patients with stable diet and weight.
While creatinine clearance, as measured by 24-hour urine estimation, is riddled with numerous practical problems that might render the test inaccurate, cystatin C, a non-glycosylated basic protein and an important cysteine proteinase inhibitor produced by all nucleated cells in the body and proposed as a potential substitute for serum creatinine, does not have the backing of all the studies done thus far in its favor either. Serum cystatin C may reflect mild renal impairment better than creatinine.(6) Macdonald and colleagues in their recent study concluded that, contrary to previous thinking, estimating GFR using cystatin C is influenced by body composition and can be improved by accounting for the same.(7)
Among the commonly used, formulaic, GFR-estimating equations (eGFR) for adults -- Cockroft-Gault (CG) and the Modification of Diet in Renal Disease (MDRD) -- MDRD is more accurate.(8),(9),(10) Currently, the abbreviated MDRD equation is widely recommended by many national and international organizations; Internet-based calculators are readily available for this calculation method. It requires just age, sex and race and avoids measurement of weight, which is not readily available in many elderly, especially those in nursing homes. Stable renal function and creatinine level are required for accuracy while using this equation.
In terms of drug dosing, validation studies are not available yet for MDRD equation, so the creatinine clearance method is still the widely used choice for drug dosing adjustments. Validation studies for MDRD are also limited for the elderly, some ethnic populations and in patients with either higher GFRs or lowest levels (e.g., the dialysis dependent).(11),(12),(13),
(14),(15),(16),(17),(18),(19),(20),(21),(22),(23) Because of its decreased sensitivity at higher GFRs, eGFR using MDRD is reported as > or <60 ml per minute per 1.73 m2.
MDRD (Abbreviated version) (mL/min/1.73m2): GFR = 186 x [SCr]M-1.154 x [Age]-0.203 x [0.742 if patient is female] x [1.212 if patient is African American]
Chronic Kidney Disease
According to the National Kidney Foundation (NKF), chronic kidney disease, regardless of its cause or diagnosis, is said to be present if:
- There is kidney damage, either structural or functional, for >3 months with or without decreased GFR. The damage could be reflected as pathological abnormalities in the kidney or its markers in blood or urine or imaging studies.
OR
- there is a decline in GFR of <60 mL/min/1.73 m2 for >3 months, with or without kidney damage.(8),(10)
The use of terms such as "chronic renal insufficiency" and "chronic renal failure" should be avoided in practice.
NKF further classifies CKD as follows:
Table 1. NKF Stages of Chronic Kidney Disease.
| Stage | Description | GFR (ml/min/1.73m3) |
|---|---|---|
| 1 | Kidney damage with normal or ↑GFR | >90 |
| 2 | Kidney damage with mild ↓GFR | 60-89 |
| 3 | Moderate ↓GFR | 30-59 |
| 4 | Severe ↓GFR | 15-29 |
| 5 | Kidney failure | <15 (or dialysis) |
* Reprinted with permission from the National Kidney Foundation.
Note that many elderly without CKD may have a GFR maintained 60 to 80 ml per minute per 1.73 m2 and are described as having "decreased GFR". Decreased GFR needs to be studied further and is seen especially among those who are on vegetarian diets, have a unilateral kidney and who are suffering from extra-cellular volume depletion states.(10)
As mentioned above, kidney damage can determine CKD presence. The markers of such damage include persistent proteinuria, abnormalities in the urinary sediment and abnormalities on imaging studies. Proteinuria occurs early and is a sensitive marker of the damage. It can be measured by dipstick method, 24-hour excretion method or by spot urine tests (protein or albumin to creatinine ratio). Spot urine albumin to creatinine ratio method is more amenable to the geriatric setting and a value of 30 to 300 mg of albumin/g of creatinine represents microalbuminuria, while a value >300 mg of albumin/g of creatinine represents clinical albuminuria. Microalbuminuria should be confirmed on 2 or 3 collections over 3 to 6 months.(24)
Recommended Actions for Different Stages of CKD
It is important to identify those at risk for CKD in order to delay its onset or slow it down, since CKD is silent in its early stages. From a geriatric perspective, risk factors for CKD include diabetes mellitus (DM), hypertension (HTN), older age, urinary tract infections, urinary stones and obstruction of the lower urinary tract. Note that certain diseases that affect the kidney such as vascultis, amyloidosis, para-protein mediated kidney disease and tubulointerstitial nephritis, especially the interstitial form, may be seen more often among the elderly.(25),(26),(27) At risk patients should be screened for kidney damage markers, their level of kidney function assessed and risk factor reduction steps should be undertaken.
Stage 1 patients need to be further assessed for the cause of CKD and treated appropriately. DM nephropathy is the most common etiology of CKD and end stage renal disease in adults, particularly among those older than 60 years of age.(3) Interventions to slow CKD include strict glycemic control in diabetics, blood pressure (BP) control in hypertensives, starting angiotensin converting enzyme inhibitors (ACEI) or angiotensin-receptor blocker (ARB) in diabetic or proteinuric or hypertensive patients.(10) Treatment of comorbid conditions and attempts to reduce cardiovascular risk reduction (CVD) should be continued.
Similarly, in stage 2 CKD, disease progression should be estimated and interventions to slow it should be attempted. At stage 3 CKD, besides the steps mentioned above, focus should be on complications as they become more evident including anemia, decreased calcium, onset of left ventricular hypertrophy (LVH), malnutrition, bone disease, etc. Therefore, anemia work up, checking nutritional parameters, checking vitamin D levels or addressing functional well being should be considered as needed. At stage 4, preparation for kidney replacement therapy should be initiated and at stage 5 it has to be generally considered.(10)
For the treatment of hypertension, ACEIs and ARBs are preferred. Thiazide diuretics in those with GFR >30 mL/min/1.73 m2, loop diuretics in those with GFR <30 mL/min/1.73 m2 and either twice daily dosing of loop diuretic or combination of loop diuretic with thiazide diuretics in those with volume expansion and edema may be considered.(10),(28) Hemoglobin A1c may under-represent glycemic state in hemodialysis patients because of decreased metabolism, anemia and shortened life span of the red cells.(29) CKD leads toan increased mortality from CVD in patients affected with it, which is the basis to place all CKD patients, irrespective of other CVD risk factors, in the highest risk group for cardiovascular risk factor reduction.(30) Cardiovascular disease is the leading cause of death in hemodialysis patients.
Erythropoietin deficiency, inflammation, blood loss from hemodialysis and vitamin deficiency may all contribute to anemia in CKD, the onset of which may be noted in stage 1 but is almost always present in stage 5 patients.(31),(32) Prior to starting therapy with any erythropoiesis-stimulating agent for anemia of CKD, other causes of anemia should be ruled out. Hemoglobin is preferred over hematocrit to monitor for anemia in CKD and if it is <12.5 mg/dl in men and postmenopausal women, and <11 mg/ dl in others, further assessment should be considered. A complete blood count, reticulocyte count, serum iron profile and stool for occult blood are reasonable initial steps.(31),(33) Erythropoietin level is not recommended in CKD-related anemia, as it is expected to be low inappropriately because the kidney is affected.(31),(34)
Erythropoiesis stimulating agent (ESA) therapy should be started in CKD patients whose anemia work up has not revealed any likely cause other than CKD itself and are either iron replete or iron deficient but unresponsive to iron supplement trial.(31) The iron levels available for erythropoiesis immediately is reflected by transferrin saturation (TSAT) and serum iron, while iron level for storage is reflected by serum ferritin. The goal of iron repletion should be to achieve levels at which the target hemoglobin level can be accomplished and maintained. This usually requires the TSAT to be >20% and a serum ferritin level of >100 ng/ml.(35)
The target hemoglobin for ESA-treated CKD patients, as recommended by the NKF, is 11 g/dL or greater but it should not be routinely or intentionally maintained at >13 g/dL because of insufficient evidence as to its clinical value.(33) However, a range of 11 to 12 g/dL is recommended by the investigators of the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial published recently. A higher target level of hemoglobin was shown in this trial to be associated with such adverse effects as increased risk of death from myocardial infarction and increased hospitalizations for congestive heart failure and stroke, without concurrent improvement in quality of life.(36)
Another trial published recently at the same time as the CHOIR trial, called the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) by Drüeke and colleagues, showed that early and complete correction of hemoglobin to a target level of 13 to 15 g/dl, did not decrease the incidence of cardiovascular events compared to a partial correction of hemoglobin to a level of 10.5 to 11.5 g/dl.(37) There are possible risks of thrombosis, vasoconstriction and worsening BP with complete correction of anemia of CKD with ESA, the mechanisms of which need further investigation.(38)
Compared to the intravenous (IV) route, ESAs are more effective by subcutaneously but IV is more convenient in hemodialysis patients. Two forms of ESAs are available currently in the U.S. including epoetin alfa and darbepoetin alfa. Initial dosing of epoetin alfa by subcutaneous route is usually 80 to 120 U/kg/week in 2 to 3 divided doses. After 4 weeks, the dose is increased by 25% if the hemoglobin has not risen by 0.3 to 0.5 g/dl per week with initial dosing or decreased by 10 to 25% if the hemoglobin level has risen by 0.6 to 0.7 g/dl/week. Worsening of hypertension, headaches and pure red cell aplasia are some of the adverse effects of erythropoietin to watch for.(39)
Darbepoetin alfa has a longer half life and higher potency compared to erythropoietin alfa and may be administered once a week, once in two weeks or once a month in some patients depending on different situations, with the initial dosing of 0.45 μg/kg/week in erythropoietin-naïve patients. The dose is then adjusted by 25% depending on change in hemoglobin level of <0.25 g/dL/week or >0.5 g/dL/week.(40)
Conclusion
The prevalence of CKD is assuming epidemic proportions and the elderly are especially prone for it. It is, therefore, important to identify the at-risk patients early, attempt risk factor reduction, assess for kidney damage markers and level of function, and make appropriate early referral to nephrologists as indicated. Staging CKD helps the clinician to focus on carrying out the recommended actions for each stage, to watch for complications and initiate treatment for them. The treatment of anemia, for instance, will improve cognition and quality of life.(41),(42) In addition, a recent retrospective study showed that untreated anemia in elderly patients with predialysis CKD was associated with a significant increase in medical costs.(43)
At each patient visit, it is also important to review carefully the medications and adjust dosages according to the kidney status, if need be. Elderly patients with CKD are more likely to be frail --- less capable of performing previously practiced social activities of daily living under stress.(44),(45) In a prospective cohort study, Fried and colleagues, showed that CKD, in fact, is associated with the development of functional impairment independent of comorbidity, body composition, and tests of strength and physical performance.(46) A multidisciplinary approach involving concerned personnel for adequate and appropriate exercise and nutrition, together with medical management of CKD, is, therefore, of utmost importance in these patients.