Acute-on-Chronic Kidney Disease R.R., A 70-YEAR·OLD, 5·FT 7·1M, 135·LB FEMALE, was admitted to the hospital 2 days ago for left lower lobe pneumonia and postprandi-al epigastric pain. She had a history of chronic obstructive pulmonary disease requiring oral steroids 2 or 3 times a year and many previous admissions for pneumonia. She had developed worsening shortness of breath and fever over the past few days. In addition to COPD, R. R. has a history of chronic kidney disease sec-ondary to diabetes and hypertension. Her SCr had typically been 2 mg/dl and her BUN 35 mg/dl. She has a history of allergies to cepha-losporins (anaphylaxis) A gram stain of sputum revealed many Gram-negative rods. Her SCr concentrations on the previous 2 days were 2.0 and 2.1 mg/dl R.R. was empirically started on tobramycin 430 mg intravenously daily. Serum drug concentrations were not ordered. Five days later, BUN and serum creatinine concentration were obtained and were 40 mg/dl and 3.5 mg/dl, respectively. Urinalysis revealed a urine sodium of 45 mEq/L, a urine osmolality of 300 mOsm and a specific gravity of 1.010. Brown, muddy granular casts were noted.

Question: How should R. R.'s kidney function be estimated? Discussion: At admission, it is reasonable that R. R.'s kidney function be assessed either by the Cockcroft-Gault and/or the MDRD equation. With a SCr of 2.0 mg/dl, the Cockcroft-Gault equation gives an estimate of approximately 30 ml/min. Question: What is the appropriate interpretation of kidney injury of R. R. on day 5? Discussion: Tobramycin is a known nephrotoxic agent. At admission, the patient was started on an extended-interval regimen. Although the dose (7 mg/kg) was appropriate, given the patient's poor kidney func-tion, the regimen should have been initiated at q 48 hr. In addition, SDCs should have been monitored more frequently during therapy. The patient has developed acute tubular necrosis. This is supported by an elevated BUN/SCr at a ratio of 10: 1. In addition, the urinalysis re-vealed relatively dilute urine. This is consistent with ATN since the renal tubules have lost their concentrating ability. Most importantly, muddy granular casts are consistent with the diagnosis of ATN.

mating Equations for GFR HENRY G., A 30-YEAR-OLD MAN (non-African American), has a sig-rificant history for diabetes mellitus type 1 . laboratory tests were as follows: Sodium, 140 mEq;t. (136--145 mEq;t.) Potassium, 4.5 mEq;t. (3.5-5.0 mEq;t.) CNoride, 101 mEq;t. (96--106 mEq;t.) Catxlil dioxide, 28 mEq;t. (24-30 mEq;t.) Ma!Jiesium, 2.0 mEq;t. (1.5-2.2 mEq;t.) GlJCose, 98 mg/dl (70-110 mg/dl)

SCr, 1.45 mg/dl (0.7-1.5 mg/dl)

Question: Why would his eGFR vary between the MORD and CKD-EPI estimating equations? Discussion: Using the MORD and CKD-EPI equations, the calculated eGFR for Henry G. are 57 ml/min/1.73 M2 (stage Ill CKD) and 64 ml/min/1.73 M2 (stage II CKD ), respectively. First, it has to be recognized that the stucly equations were developed in different populations. The MORD was developed in patients with CKD (average eGFR 40 ml/min/1.73 M2) and the CKD-EPI in more diverse patients with and without kidney disease (average eGFR 68 ml/min/1 . 73 M2) . In a recent systematic reviev-t, inherent biases were identified in both equations. The MORD exhibited more bias at eGFR greater than 60 ml/min/1.73 M2 and the CKD-EPI at eGFR less than 60 ml/min/1 .73 M2. One universal equation has not been found to be optimal for all populations or ethnic populations. The CKD-EPI equation may permit more effective utilization of resources by oo'ter 1'deriMtatiiaa ol t.7ose µ7t.ients sha1ld be i..1rx.ie.r t.i'Je care of a nephrologist. 37

MINICASE 2

Heart Failure RUTH K., AM 83-YEAR·OLD FEMALE with a long history of congestive heart failure, was admitted to Community Hospital with complaints of shortness of breath (she needed to sleep in her recliner and was un-able to sleep in her bed despite using two pillows), 15-pound weight gain, and fluid retention in her lower extremities. She also had anorexia, nausea, fatigue, and weakness. All had worsened over the past 2 weeks. PMH: hypertension, osteoarthritis, atrial fibrillation Physical examination revealed a frail (5'3"; 78 kg) woman in moderate distress; heart rate of 108 BPM; BP of 96/60 mm Hg; S3/S4 heart sounds; + three pitting edema bilateral lower extremities. Chest x-ray reveals bilateral pleural effusions. Current medications: Lisinopril, 20 mg PO daily Metoprolol succinate, 100 mg PO daily Furosemide, 40 mg PO daily KCI, 10 mEq PO BID Ibuprofen, 400 mg PO 4 times daily PRN for knee pain Laboratory tests were as follows: Sodium, 130 mEqJl (136-142 mEqJL) Potassium, 3.2 mEqJL (3.8-5.0 mEqJL) Chloride, 96 mEqJl (95-103 mEqJl) Carbon dioxide, 30 mEqJl (24-30 mEqJL or mmolA.) Magnesium, 1.3 mEqJL (1.3-2.1 mEqJL) Glucose, 78 mg/dl (70--11 O mg/dl) Hemoglobin (Hgb), 11.5 g/dl (12.3-15.3 g/dl) BUN, 76 mg/dl (8-23 mg/dl) SCr, 2.5 mg/dl (0.6-1.2 mg/dl) Urinalysis: normal BNP: 1200 pg/ml ( < 100 pg/ml) Over the next 2 days, Ruth K. received aggressive diuretic therapy (fu-rosemide 80 mg IV twice a day), and all electrolyte abnormalities were corrected. Her physical exam was much improved. She was no longer short of breath. On the morning of day 4, her test results were Sodium, 135 mEqJL Potassium, 3.2 mEqJL Chloride, 100 mEqJL Carbon dioxide, 34 mEqJL Magnesium, 1.4 mEqJL Glucose, 80 mg/dl Hgb, 11.4 g/dl BUN, 35 mg/dl SCr, 1. 4 mg/dl BNP, 400 pg/ml

Question: What type of renal dysfunction was Ruth K. experiencing on admission to the hospital? What were the likely causes of her elevated BUN and SCr? How often should BUN and SCr be interpreted? Discussion: This case is rather complex because of the involvement of the kidneys in heart failure. Initially, the elevated BUN and SCr could be attributed to a prerenal state secondary to increased edema (hy-pervolemia) caused by worsening heart failure. This is supported by her clinical presentation (weight gain, symptoms of heart failure, CXR, elevated BNP, and an elevated BUN:SCr ratio with a ratio of greater than 20: 1. The urinalysis did not reveal any cells that might indicate an intrinsic acute kidney injury (see Urinalysis section). In addition, diuretics may increase the BUN, which may complicate the picture, but the other evidence supports the diagnosis of prerenal azotemia. Assessment of kidney function on day 1 is difficult since the Cockcroft-Gault, MDRD, or CKD- EPI equations should not be used in patients with acute alterations in kidney function. In suspected acute kidney injury and when there is a need to assess GFR, measurement of CrCI through collection of urine should be considered. Question: What was the trigger of Ruth K.'s heart failure? Discussion: Ruth K. has several risk factors that can worsen heart failure. She has a history of hypertension and atrial fibrillation. She may have been using more ibuprofen more frequently and for an extended period for increased osteoarthritic knee pain. Additional risk factors that could also contribute to exacerbation of heart failure include noncompliance with fluid restriction (2 liters) and diet (2 g sodium/day). Question: What other electrolyte abnormalities resulted? Discussion: There are several electrolyte abnormalities identified during initial presentation and then subsequent lab analysis: increased BUN and SCr, increased serum bicarbonate, hypokalemia, hypomagnesemia, and hyponatremia. On admission, worsening heart failure resulted in de-creased RBF As with creatinine, there will be a reduction in BUN filtration at the glomerulus; however, urea is avidly reabsorbed in the proximal tubule (following sodium and water) resulting in an elevated ratio of BUN out of proportion to the creatinine (>20:1). Ruth K. also present-ed initially with hypervolemic hyponatremia. This most likely caused by the worsening heart failure, diminished blood flow to the kidney, and peripheral edema and subsequent weight gain. As Ruth K. becomes euvolemic, the hyponatremia will gradually be corrected. After aggres-sive diuresis with IV furosemide, hypokalemia and hypomagnesemia required replacement therapy. Loop diuretics can also cause metabolic alkalosis (increased serum bicarbonate). Overaggressive diuresis can cause elevations in BUN and SCr without evidence of overt heart failure.

MINICASE 3

Renal Drug Dosing JANEL., A 75·YEAR·OLD, 5'6", 175-LB FEMALE, was admitted to the hospital from a long-term care facility where she has been residing after hip fracture surgery 2 months ago. She usually looks forward to her physical therapy sessions and participates in many resident group activities. Recently, on the day of admission she had been lethargic, confused, and needed assistance with eating and dressing. Vital signs were BP 100/60, HR 110, and temperature 96°F. Jane L. has a PMH of long-standing CKD secondary to diabetes and hypertension. Her SCr had typically been 2.40 mg/dl and her BUN 45 mg/dl. She is allergic to ciprofloxacin, which causes hives. A urine analysis demonstrated > 100,000 cfu, WBC 40, and nitrite and leukocyte esterase were positive. Culture and sensitivity revealed Pseu-domonas aeruginosa sensitive to imipenem and ciprofloxacin. Empiric therapy with imipenem 500 mg IV q 6 hr was initiated. Three days later Jane l. suffered a seizure; BUN and SCr concentra-tion were obtained and were 40 mg/dl and 2.50 mg/dl, respectively. Upon recognition of this reaction from improperly dosed imipenem, the physician discontinues the imipenem and orders IV tobramycin as per hospital pharmacist.

Question: How should Jane L's kidney function be estimated to dose tobramycin? Discussion: The most conservative estimation of CrCI should be used to dose this known nephrotoxic medication. The National Kidney foun-dation has suggested the use of either the CG or the MORD equation to dose drugs eliminated by the kidney. In this scenario, all of the esti-mations of CrCI are relatively close, between 18-24 ml/min. The most

conservative estimate of 18 ml/min should be used to calculate/estimate tobramycin dosing. Cockcroft-Gault TBW: (140 - age) x wt (kg) x 0.85 (female)= 24 ml,.tnin

72 x SCr Cockcroft-Gault IBW, where IBW (kg) = (2.3 x inches >5 feet) + 50 (if male), or (2.3 x inches > 5 feet) + 45.5 (if female) = 18.2 ml/min MORD (ml/min/1.73 M2) = 175 x Ser-1 154 x age-0 203 x 1.21 (if African

American) x 0.7 42 (if female)

= 19 ml/min/1.73 M2

Individualized MDRD: eGFR/1 . 73 m2 x estimated BSA (m2) = eGFR for drug dosing= 19 ml/min/1.73M2 x1.923 M2 = 21.1 ml/min

CKD-EPI: GFR= 141 x min CSJK, 1)" x max (Sc/K, 1Y1209x 0.993ase x 1.018 (if female) x 1.159 (if African American) = 18 ml/min/1. 73 M2

Question: What dose and inter.-a1 of tobramycin should be recom-mended? Discussion: Jane L. is not a candidate for once-daily aminoglycoside dosing since CrCI is less than 60 ml/min. More conventional dosing of tobramycin is appropriate with the frequency adjusted for her de-creased renal function and a goal peak of 4--5 and a trough of 0.5. A loading dose of 1 mgtkg is based on her total bocly weight. The main-tenance dose should be adjusted based on changes in BUN, SCr, and pharmacokinetic analysis of drug levels usually beginning with the third dose every 3-4 days. Therefore, Jane l. should receive a loading dose of 1 mg;kg (80 mg); then for a GFR 10--50 ml/min, she should receive a maintenance dose of 30% to 70% of the loading dose every 12 hours. 49