Spinning the Urine

Motivation: Tonight, at 8 pm, I was trudging up stairs with an empty stomach and one last task to do - looking at urine sediment under the microscope.  But, is urine microscopy a useful heritage of the past?  I was trying to use urine microscopy to distinguish pre-renal injury from acute tubular necrosis, which are often the most debated diagnoses in an inpatient setting.  How good is urine microscopy for such a purpose?  Turns out that these grumbling musings have been studied more conclusively in a prospective study.

Paper: Perazella, M.A., Cocoa, S.G., Kanbay, M. et. al. "Diagnostic Value of Urine Microscopy for Differential Diagnosis of Acute Kidney Injury in Hospitalized Patients." Clin J Am Soc Nephrol (2008) 3: 1615-1619.

Methods: At Yale-New Haven Hospital between April 2006 and May 2007, 267 inpatient nephrology consults were called for acute kidney injury.  Prior to looking at urine sediment, the nephrologists were asked to provide a "pre-test" clinical diagnosis consisting of: (1) ATN, (2) pre-renal azotemia, or (3) other.  Nephrologists could use all available information including trends in serum creatinine.  Subsequently, after patient discharge, renal biopsy, or death, nephrologists were asked to provide a "final" diagnosis.

Results:
ATN vs Pre-renal: Overall in "final" diagnosis, 123 patients were diagnosed with ATN and 108 patients with prerenal AKI. Using the "final" diagnosis after hospital course as gold standard, the performance characteristics of urine microscopy in distinguishing ATN vs pre-renal AKI are as follows:
- sensitivity: 0.76
- specificity: 0.86
- positive likelihood ratio: 5.75

On further subgroup analysis, the authors looked at specific findings in urine microscopy most helpful in distinguishing ATN from pre-renal AKI (expressed in terms of likelihood ratio for ATN):
Granular Casts per High Power Field (40x magnification) +LR for ATN vs Prerenal:
0 ------------ LR: 0.23
1 to 5 ------- LR: 2.97
6 to 10 ------ LR: 9.68
>10 --------- LR: Infinite (No instances in pre-renal cases)
Note that granular casts did not have to be muddy brown!

Renal Tubular Cells per High Power Field +LR for ATN vs Prerenal:
0-------------- LR: 0.72
1 to 5 --------- LR: 1.97
6 to 20 -------- LR: Infinite (No instances in pre-renal cases)
>20 ----------- LR: Infinite (No instances in pre-renal cases)

Concordance: Between "pre-test" and "final" diagnosis, the concordance for diagnosis of pre-renal AKI was 77% while the concordance for ATN was 86%.

Discussion: I found this paper useful in a couple of different ways.  First, I thought that the microscopic equivalent of ATN was muddy brown casts.  Seeing a lot of granular casts or many renal tubular cells predicts ATN just as strongly!  Secondly, urine microscopy remains useful.  Overall initial clinical assessment of pre-renal AKI is wrong about a quarter of the time - an error rate that is pretty high.  Observing many granular casts or renal tubular cells can certainly help reduce this error rate.

This paper, while helpful, has some curious methodological limitations.  The authors had the nephrologists give a "pre-test" diagnosis.  However, no "post-test" diagnosis was assessed after urine microscopy.  That way, the effect of urine microscopy on diagnosis could be better assessed.  Also, the "final" gold standard diagnosis used is an overall clinical assessment and not a renal biopsy, which could significantly change the diagnoses.  

From Heart Failure to Renal Failure - The Myth

Motivation: Ever since the week on heart failure in second year of medical school, I have been thinking about congestive heart failure (CHF) as consisting of "backup" symptoms like dyspnea and edema or "forward flow" symptoms like somnolence and fatigue.  One of the CHF exacerbation symptoms that I usually categorize under forward flow  is renal failure.  The presumed explanation for renal failure is relative renal hypoperfusion from decreased cardiac output in acute CHF exacerbation.  Recently, I learnt about some trials that challenged this view.  Here is one of the trials:

Paper: Nohria, A., et. al. Cardiorenal Interactions: Insights From the ESCAPE Trial. J. Am. Coll. Cardiol.(2008) 51: 1268-74.  http://content.onlinejacc.org/cgi/content/full/51/13/1268

Methods: The ESCAPE trial was a randomized trial comparing pulmonary artery catheter versus clinical volume assessment based treatment for acute heart failure exacerbation.  Included patients had LVEF<30% with SBP<125 mmHg with signs and symptoms of acute heart failure.  Patients with baseline creatinine >3.5 mg/dL  were excluded.  The current paper was an ad hoc analysis of baseline hemodynamic parameters from pulmonary artery catheter measurements and serum creatinine.

Results:
Subjects: In general, the mean age of the patient group was 56 with serum creatinine of 1.5.  Most of the patients were getting an ACE-I/ARB and beta-blocker.

Hemodyamic Correlation: There was no correlation between baseline serum creatinine or estimated GFR and cardiac index, systemic vascular resistance, or wedge pressure!  There was a weak but significant correlation between baseline serum creatinine and right atrial pressure (r = 0.165, p = 0.03).  Similar correlation was found between baseline estimated GFR and right atrial pressure (r = -0.195, p = 0.01), meaning higher right atrial pressures were correlated with decreased GFR.

Discussion: This paper clearly calls into question the assumption that renal dysfunction from acute heart failure is directly linked to renal hypoperfusion.  Renal failure seen in acute heart failure is being increasingly called the "cardiorenal syndrome" in recognition of the more complex pathophysiology.  Rather than renal arterial hypoperfusion, this trial along with other evidence suggests that elevated venous pressures may directly compromise renal function.  One of the problems in extrapolating from trials like this is the complexity of interacting factors.  The patients in this trial were sick and being treated with multiple agents like beta-blockers and ACE-I/ARB that also affect the renal vasculature.  But, these pharmacologic confounders would be expected to affect vascular tone, and no correlation was found between  systemic vascular resistance and renal dysfunction either.  Besides the effects of elevated venous pressure, other possible explanations for renal dysfunction include undefined direct toxic effects of therapeutic agents.  Also, many processes that worsen CHF, like HTN and diabetes, also have pathologic effects on the kidneys.  In the coming years, we will likely learn more about the complex pathophysiology of cardiorenal syndrome!