The end of the road for urinary eosinophils?

Nate wrote a couple of posts in the past about the use (and misuse) of urinary eosinophils for the diagnosis of acute interstitial nephritis (AIN). Since the original report describing the use of this test in the NEJM in 1986, a number of papers and commentaries have been published that cast doubt on its true effectiveness. A paper was recently published in CJASN that looked at the accuracy of this test in a series of patients who had kidney biopsies for AKI between 1994 and 2011.

The authors examined the biopsy and urine results of 566 patients who had biopsies and a urinary eosinophil test over the course of the study. Overall 91 patients had biopsy-confirmed AIN, 73 of whom were considered to be drug-induced. 31.6% of patients had UE>1%, the traditional cut-off for the diagnosis of AIN. The majority of these did not have AIN and the distribution of positive UE was uniform across diagnoses. As a result, the sensitivity and specificity of this test for the diagnosis of AIN were poor. Using 1% UE as a cut-off, the sensitivity was 30.8% and the specificity was 68.2%. The PPV was 15.6% and the NPV was 83.7%. Using a more stringent cut-off of 5%, the sensitivity decreased to 19.8%, the specificity, PPV and NPV were 91.2%, 30% and 85.6% respectively.

One significant limitation of this study was that it was restricted to patients who had kidney biopsies and the majority of patients with suspected AIN do not have kidney biopsies. However, I would imagine that this should bias the results towards favoring UE as a test as presumably patients with more severe disease would be more likely to have a biopsy. Another issue is the potential that there was a bias towards biopsying patients who did not have UE (and so were not thought to have AIN in the initial impression). This could have the effect of reducing sensitivity.

Notwithstanding this, the fact that the distribution of positive UE was so well distributed among the various diagnoses combined with the very low sensitivity of this test would suggest that the use of this test should no longer be routine in the diagnosis of AKI. At best, a negative test helps rule out AIN in patients with a low pre-test probability while a positive test is not particularly useful. As the authors of the accompanying editorial point out, even in drug-induced AIN, the infiltrate may not have a high proportion of eosinophils, suggesting that in many cases there may not even be a plausible biologic rationale for this test.

Kidney Biopsy Case: AKI

A 54 year old man was referred to the Nephrology service due to AKI after presenting with lethargy and severe thirst. He had a long history of pulmonary and hepatic sarcoidosis which had been quiescent for some time. He likely had some baseline mild CKD with a serum creatinine of 1.3 mg/dl and 0.5 g/day proteinuria. His medications were unremarkable except for a calcium and vitamin D preparation which he had been taking for several months. His creatinine was 4.0 mg/dL and calcium was 13.5 mg/dl on presentation. He was volume resuscitated, treated for his hypercalcemia and proceeded to renal biopsy. Low power light microscopy is below which reveals an interstitial infiltrate with moderate fibrosis and some sclerosed glomeruli.

Higher power demonstrates multiple non-caseating granulomas. The granulomas consist of amorphous reddish material as well as multi-nucleated giant cells (below; top left and right of center).

Another example below of a granuloma (on the left of the panel) in a sick looking tubulo-interstitium.

The diagnosis was sarcoidosis-related granulomatous interstitial nephritis. He was commenced on high dose oral steroids and his renal function settled back down to normal over several weeks. Sarcoidosis does uncommonly affect the kidneys and is a major differential for granulomatous interstitial nephritis (see previous post). A teaching point for this case is not to presume the hypercalcemia is all iatrogenic. The high calcium points to sarcoid activity which was demonstrated nicely on the biopsy.

Lead Nephrotoxicity

I saw a patient in the clinic who was referred for evaluation by his PCP with CKD, a bland urine sediment and a history of hyperuricemia and gout. He had no history of diabetes or hypertension and had no obvious (to me) reason for his CKD at first glance. He was a non-smoker and had no family history of renal disease. He worked as a plumber and his examination was entirely normal.

My attending came in and asked him if he was still using as much lead these days as he had in the past – apparently he was down to 4 times monthly. He was using it to fix joints and was regularly exposed to lead vapor. Even at this, his exposure was significantly less than it had been when he was younger before work practices changed.

Lead toxicity is an under-recognized cause of chronic kidney disease. Commoner in the past when lead was ubiquitous and likely less important now as an environmental cause of renal disease, it should be suspected in people who still work with lead regularly (or had a significant past exposure). Plumbers, fishermen (who make their own weights) and hunters (who make their own shot) continue to be at risk.

The renal signs of lead toxicity depend on the duration and degree of exposure. Acute lead toxicity leads to proximal tubular inclusions and an acute fanconi syndrome. Chronic lead toxicity causes a chronic interstitial nephritis with a relatively bland urine sediment. Patients typically have gout and this condition has sometimes been confused with uric acid nephropathy. Even low levels of lead exposure appear to be associated with a decline in GFR. A study in 1992 in the NEJM found that a 10-fold increase in blood lead concentration was associated with a 10-13mls/min decline in GFR in a population of asymptomatic patients. There is a chicken and egg issue here however, as a lower GFR can lead to decreased lead excretion.

The diagnosis is made by first determining if the patient has been exposed to significant amounts of lead and then measuring lead levels in the blood. In patients with a historic exposure, this may not be reliable because of sequestration in the bone and x-ray fluorescence is more reliable.

The treatment involves removing the sources of exposure and, in patients with substantial lead toxicity, chelation therapy. This is not entirely without risk and has been associated with acute renal failure in children. Chelation in the presence of ongoing exposure will actually increase toxicity as it will lead to an overall increase in blood levels.

We are in the process of getting the XFR scan for this patient and it may be that he does not have lead toxicity after all; but it is definitely one to think about in the future.