A 30-year-old African American female student is referred to you for evaluation of hematuria. Urinalysis shows >20 RBCs per high power field. There is no proteinuria. Repeat urinalysis 1 month later shows similar number of RBCs. There are no RBC casts. Her hematuria is unrelated to her menstrual cycle. BP is 120/78 mmHg. Serum creatinine is 1.0 mg/dL. She weighs 60 kg. Renal ultrasound reveals large kidneys with multiple cysts. She wants to know whether or not she has kidney disease. Which one of the following statements is CORRECT regarding her renal condition?

In order to provide a uniform definition of CKD, the Kidney Disease Outcome Quality Initiative (KDOQI) of the National Kidney Foundation defined CKD as kidney damage (with or without decreased GFR) or decreased GFR <60 mL/min/1.73 m ² for >3 months. Kidney damage is defined as pathological abnormalities or markers of damage including abnormalities in blood or urine tests or in imaging studies. Based on the above definition, the patient has microscopic hematuria and large kidneys with cysts. Thus, she is considered to have CKD. Therefore, option D is correct. The eGFR may place her in stage 2 CKD. According to Cockcroft-Gault equation, the calculated GFR is 78 mL/min. She needs follow-up by a nephrologist for evaluation of adult polycystic kidney disease.

The KDIGO (Kidney Disease Improving Global Outcomes) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease also developed similar criteria to define CKD. In this guideline, CKD is defined as “abnormalities of kidney structure or function, present for >3 months with implications for health.” The following table (Table 4.1 ) shows the KDIGO recommendations for CKD definition.

Regarding the prevalence of CKD in the USA from NHANES (National Health and Nutrition Examination Survey) and USRDS (United States Renal Data System), which one of the following statements is INCORRECT?

Coresh et al. have examined in a cross-sectional analysis (assessment at a single point of time) of the prevalence of albuminuria (>30 mg/g creatinine) and eGFR by MDRD formula in NHANES population who were 20 years and older between 1988–1994 and 1999–2004. The analysis showed that the prevalence of CKD stages 1–4 increased from 10 % in 1988–1994 to 13.1 % in 1999–2004. A higher prevalence of diabetes, hypertension (HTN), and body mass index (BMI) accounted for the entire increase in the prevalence of albuminuria. The presence of albuminuria rather than a decrease in eGFR alone seems to be the reason for the increase in prevalence of CKD. Thus, a combination of both albuminuria and eGFR should be considered in the determination of early stages of CKD, as suggested by some investigators. Thus, statements A to D are correct.

Statement E is incorrect because albuminuria is most prevalent in adult subjects ≥60 years of age and in African Americans and in those with diabetes and HTN. The following Table 4.2 shows the prevalence of CKD stages 1–5 in the USA.

Which one of the following is NOT a traditional risk factor for cardiovascular disease?

Except for albuminuria, the remaining factors have been reported as traditional risk factors, as suggested by the Framingham study. The following table lists both traditional and nontraditional risk factors for CKD as well as cardiovascular disease (CVD), suggesting that both CKD and CVD share similar risk factors (Table 4.3 ) .

A 40-year-old man with HTN is referred to you for evaluation of his risk for progression of kidney disease. His BP is 140/80 mmHg. His serum creatinine is 1.8 mg/dL (eGFR 59 mL/min) and a 24-h urine albuminuria of 200 mg. He has no diabetes and comorbid conditions. According to KDIGO Guideline, how would you classify his risk of kidney progression?

The KDIGO Guideline recommends in any CKD patient to identify the cause of CKD, GFR category, albuminuria category, and other risk factors, including comorbid conditions in predicting prognosis of CKD. Tables 4.4 and 4.5 help predict the prognosis of this patient’s kidney progression.

From the above tables, this patient with CKD is at high risk for progression of his kidney disease. Thus, option C is correct.

Of the following independent risk factors for ESRD in the RENAAL (Reduction of Endpoints in NIDDAM with the Angiotensin II Antagonist Losartan) study, which one is identified as the strongest single predictor of ESRD?

Multivariate analysis of data from 1513 subjects with diabetic nephropathy included in the RENAAL Study identified all of the above variables as risk factors for ESRD. However, albuminuria remained as the strongest single predictor of ESRD. Thus, option D is correct.

Regarding awareness of CKD among patients, which one of the following statements is FALSE?

CKD is usually recognized incidentally in most of the subjects, and the management becomes rather difficult to prevent its progression to ESRD. One major problem is awareness of the disease. Several studies assessed awareness of CKD, which showed that the level of awareness by both patient and provider is unacceptably low. Although about 90 % of patients with CKD had seen a physician within the previous year in the KEEP, awareness of their disease was low for all stages of CKD. However, awareness was profoundly increased among patients with CKD stages 4–5 compared to stages 1–3. Thus, options A and E are correct.

In a cross-sectional study using an online questionnaire survey among 479 PGY 1, PGY 2, and PGY 3 internal medicine residents of the USA, Agrawal et al. reported that half of the residents did not know that proteinuria for 3 or more months defines CKD, and one-third did not know the staging of CKD. However, most residents knew the traditional risk factors and goal BP for CKD. Also, most residents chose to refer a patient with eGFR <30 mL/min to a nephrologist. Thus, it is important to improve education among residents for better understanding of CKD and its management. Thus, option D is false.

Many edible plant products have been implicated in the development of CKD. Match the following plant-derived compounds that are associated with the documented chronic kidney disease (CKD)?

CKD has been described in association with ingestion of many plant-derived compounds, usually called herbal medicines. The use of herbal medicines has increased throughout the world, and accounts for approximately 20 % of the overall drug market. These herbal medications produce a variety of tubular and tubulointerstitial diseases (TIDs).

Aristolochic acid is derived from the plant Aristolochia spp. This compound causes TID, acute and chronic renal disease. Also, uroepithelial malignancies have been described with the ingestion of the Aristolochia spp.

Nordihydroguaiaretic acid is derived from the leaves of creosote bush, Larrea tridentata , which is a Native American shrub and used in tea. In addition, its roots and leaves are distributed in the pill form as chaparral. Nordihydroguaiaretic acid is an antioxidant and also inhibits cell division, and its long-term use is implicated in the development of renal cysts and renal cell carcinoma.

Salicin is the toxic component of the plant, Salix daphnoides , and metabolizes to salicylate. It is usually called willow bark and causes renal papillary necrosis. Yohimbine is derived from the plant, Pausinystalia yohimbe . Chronic ingestion of yohimbine causes lupus nephritis, which responds to steroids. Anthraquinone is a toxic product of the plant, Rhizoma rhei. It is commonly called rhubarb and causes chronic TID.

Compared with the Modification of Diet in Renal Disease (MDRD) Study equation, the CKD-EPI (chronic kidney disease-epidemiology collaboration) equation has several advantages. Which one of the following statements is INCORRECT regarding the CKD-EPI equation ?

Except for statement B, all other statements are correct. The CKD-EPI creatinine equation was developed using the same variables as the MDRD equation in a total of 8254 participants in ten studies (equation development data set) and 3896 participants in 16 studies (validation data set). Using the CKD-EPI equation, the median estimated GFR was 94.5 mL/min/1.73 m ² (simply referred to as mL/min) as compared with 85.0 mL/min using the MDRD Study equation. Also, the prevalence of CKD with the CKD-EPI equation was 11.6 % as compared with 13.1 % using the MDRD Study equation. Thus, the CKD-EPI equation has lower rather than higher false-positive diagnoses of CKD. Thus, the statement B is incorrect.

At least two independent studies, namely, the ARIC (Atherosclerosis Research in Communities) and the AusDiab (Australian Diabetes, Obesity and Lifestyle Study), confirmed the observations of the CKD-EPI equation. In both studies 43.5 and 25 % participants with CKD stage 3a (eGFR 45–59 mL/min) were reclassified as having no CKD. Thus, the CKD-EPI equation is more accurate than the MDRD Study equation in classifying CKD.

An 89-year-old cachectic woman is transferred from the Nursing Home for evaluation of fever and tachycardia. She weighs 50 kg. Her urine culture grows E. coli that is sensitive to gentamicin only. Her lying and sitting BP and pulse rate are suggestive of orthostatic changes. Her serum creatinine is 0.9 mg/dL and eGR is >60 mL/min. Which one of the following equations/tests is more useful in adjusting the gentamicin dose?

The MDRD Study equation has not been validated in the elderly and females (>70 years), and overestimates GFR in individuals with GFR >60 mL/min. Estimation of 24-h creatinine clearance is useful, but not practical at bed side. Iothalamate clearance involves radioisotopes and expensive as well as time-consuming. Also, it is not practical in drug dosing. Schwartz equation [GFR (mL/min/1.73 m ² ) = 0.55 × Ht (cm)/serum creatinine (mL/dL)] is applicable to children but not adults. Therefore, the only formula that is useful for drug dosing at bed side is the Cockcroft-Gault equation, which provides approximate endogenous creatinine clearance in mL/min.

The formula to calculate creatinine clearance ( C _cr ) is as follows:

Thus, the calculated C _cr is approximately 34 mL/min, which is much different from the reported eGFR of >60 mL/min. Thus, gentamicin dose needs to be reduced in this patient. Therefore, option B is correct.

Although it has been shown that the MDRD Study equation is as good as Cockcroft-Gault equation in drug dosing by Stevens and Levey, a kinetic model by Spruill et al. demonstrated that the MDRD Study equation in the elderly overestimates renal function, leading to possible drug overdosing and drug toxicity.

A 30-year-old obese woman is admitted for management of acute exacerbation of asthma. She weighs 400 lbs. Her serum creatinine is 0.8 mg/dL. Which one of the following is the BEST method to assess her renal function?

The MDRD Study equation can be used, but it has limited validation in extremely obese individuals. The Cockcroft-Gault equation overestimates creatinine clearance unless ideal body weight is calculated, which is difficult in many patients. Serum creatinine and BUN are not good markers of renal function in obese individuals with low muscle mass. The presence of elevated creatinine and albuminuria reflects kidney disease rather than kidney function. Determination of 2 or more 24-h urine creatinine clearances is the better approach to evaluate renal function in extremely obese individuals. However, this method can also overestimate GFR. Of all the above options, option E seems appropriate.

The MDRD Study equation is a useful method to estimate GFR in which one of the following groups?

The widely accepted and approved serum creatinine-based method of estimated GFR is the MDRD Study equation. Also, this equation has been adequately validated in CKD population, including African Americans, diabetics and kidney transplant recipients who have low GFRs (<60 mL/min). Despite its wide acceptance, the MDRD formula still has several limitations, as shown in the following table, and suggests the use of clearance methods (Table 4.6 ).

Measurement of serum cystatin C as a marker of GFR has been reported to be more accurate and precise than serum creatinine in which one of the following conditions?

Cystatin C is a nonglycosylated cysteine proteinase inhibitor with a molecular weight of 13 kDa. It is secreted at a constant rate by all nucleated cells. Cystatin C is freely and totally filtered at the glomerulus without peritubular uptake. After filtration, the proximal tubules reabsorb and catabolize virtually all of cystatin C in lysosomes. Therefore, its secretion and presence in urine is negligible. Because of its absence in the urine, the clearance of Cystatin C cannot be measured but its serum concentration is considered a good measure of GFR. Unlike serum creatinine levels, cystatin C levels are not influenced by muscle mass or malnutrition.

Several studies reported that serum cystatin C levels have higher diagnostic accuracy and precision than serum creatinine levels, particularly in children, elderly, diabetics, pregnant women, and patients with cirrhosis. Thus, option E is correct.

It has been shown that determinations of both serum creatinine and cystatin C may be a better reflection of GFR than either measurement alone.

Which one of the following factors is NOT associated with elevated levels of cystatin C?

A number of factors have been shown to influence cystatin C levels. Older age, male gender, glucocorticoids and hyperthyroidism, cigarette smoking, and elevated CRP levels were independently associated with elevated serum cystatin C levels. Also, greater weight and height, neonates under 30 days of age, and asthmatics were found to have high cystatin C levels. In contrast, cyclosporine has been shown to decrease cystatin C levels (D). Also, hypothyroidism causes low levels of cystatin C.

A 50-year-old nonobese man with hypertensive nephrosclerosis has eGFR of 30 mL/min/1.73 m², as calculated by the MDRD Study equation. He wants to know how soon he needs renal replacement therapy. Which one of the following statements is CORRECT regarding the slope of decline in renal function?

The rate of GFR loss in CKD stages 3–5 patients remains unclear. However, a few studies addressed this issue in both diabetic and nondiabetic patients. A study by Xie et al. calculated the eGFR slope of decline in renal function in the MDRD Study participants with measured GFR between 25 and 55 mL/min and a median follow-up of 2.6 years. They found that the eGFR tended to underestimate measured decrements in GFR by 28 %. For example, the mean of measured GFR slope was −3.9 mL/min/1.73 m ² as compared with the mean of eGFR slope of −2.8 mL/min/1.73 m ² , representing an underestimation of 28 %. Thus, option B is correct. In some studies, both MDRD Study equation and Cockcroft-Gault equation yielded similar slopes of decline in renal function. 24-h urine creatinine clearance is not a good indicator of GFR in CKD patients, as it overestimates GFR because of high rates of creatinine secretion by the proximal tubule in CKD patients.

Since serum creatinine is influenced by muscle mass, diet, and other variables, it is believed that its measurement only or 24-h creatinine clearance may be incorrect in following the progression of kidney disease. Therefore, creatinine or cystatin C-based equations have been used to monitor GFR changes longitudinally over time in clinical and research practice. Which one of the following statements is INCORRECT regarding these equations and progression of kidney disease in CKD patients from several studies?

Serum creatinine or cystatin C-based equations are extremely important in assessing the decline in renal function over a period of follow-up in CKD patients. This follow-up is important in making treatment decisions. Lee et al. conducted a multicenter trial in Australia and New Zealand, and compared the slopes of decline in renal function in 155 patients with CKD stages 3–5 using radionuclide-measured GFR and eGFR calculated from four equations (4- and 6-variable MDRD Study equations and C-G equation with or without correction for body surface area) at baseline, 12 and 24 months. The data showed that the 2 MDRD equations initially underestimated GFR and the 2 C-G equations overestimated GFR. The MDRD Study equations showed a sustained advantage in estimating renal function longitudinally than the C-G equations.

In the AASK Study, the agreement of the eGFR-based outcomes with iothalamate clearance-based outcomes was similar when the MDRD Study equation was used instead of the AASK equation.

Perkins et al. followed 30 type 2 diabetic patients with GFR >20 mL/min/1.73 m ² , and their GFR was measured by iothalamate clearance and serum cystatin C levels at baseline and yearly for 4 years. Both measures were concordant and had similar slopes (or annual percentage changes) in 20 patients who showed a decline in renal function. In contrast, creatinine-based equations had poor correlations in slopes compared to iothalamate clearances. Thus, the authors concluded that serial determinations of serum cystatin C levels, plotted as 1/cystatin C × 100, can detect accurately the level of decline in renal function during follow-up of type 2 diabetic patients.

Regarding late referral of CKD patients to nephrologists by primary care physicians or general practitioners, which one of the following patient and health system characteristics is INCORRECT?

Late referral is usually considered an appointment with a nephrologist <4 months of starting a renal replacement therapy. A number of studies have evaluated the pros and cons of late referral. There are several barriers that cause late referral, including old age, comorbidities, race other than Caucasians, lack of insurance, poverty, and lower level of education. Thus, option B is incorrect.

Thus, patient-, health care system-, and physician- related factors were found to be potential barriers for early referral.

As an internist, you are following a 50-year-old man with HTN for 10 years. Currently, the patient has stage 4 (GFR 15–29 mL/min) CKD. You refer this patient to a nephrologist for consultation and co-management because of which one of the following reasons?

The K/DOQI Clinical Practice Guidelines for CKD suggest that “People with CKD should be referred to a specialist for consultation and co-management if the clinical action plan cannot be prepared, the prescribed evaluation of the patient cannot be carried out or the recommended treatment cannot be carried out. In general people with GFR <30 mL/min/1.73 m ² should be referred to a nephrologist.” The clinical action plan for stage 4 CKD is to prepare for kidney replacement therapy. This defines early referral.

A 20-year-old college student with a family history of adult polycystic kidney disease and her mother on hemodialysis seeks your advice and follow-up by you. Based on her family history, you consider her to be at increased risk for CKD. Which one of the following appears to be the BEST protocols for this individual?

The Kidney Disease Outcome Quality Initiative (KDOQI ) of the National Kidney Foundation recommends that individuals without kidney damage and with normal or elevated GFR, who are at increased risk for development of CKD, should have: (1) routine heath examination; (2) estimation of their renal function (eGFR); (3) testing for markers of kidney damage; (4) periodic examination; and (5) follow-up in a program of risk factor reduction, if appropriate, as in the above case. Thus, option E is correct.

A 40-year-old African American woman is being followed by an internist for management of HTN for 10 years. Her eGFR is 28 mL/min. She has a good medical insurance. Despite a 4-drug regimen (Amlodipine 10 mg, hydrochlorothiazide (HCTZ) 50 mg, Bidil (combination of hydralazine and nitrate) 1 tablet twice daily and Metoprolol 50 mg twice daily), her BP is >140/90 mmHg. Referral of this patient to a nephrologist may improve which one of the following conditions?