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.

CKD after AKI in the ICU

I give a regular talk to the residents in the ICU on CRRT and one of the things that I focus on is prognosis. We all know that the outcomes of patients requiring CRRT in the ICU are poor. Multiple studies have shown that the mortality is 40-60% and that this mortality rate has not changed in the last 20 years. However, something that residents are less aware of is that, in the event that a patient survives their stay in the ICU, the majority will not require long term dialysis - approximately 80%. This is sometimes difficult to appreciate when you see patients on HD at discharge from the ICU but most of these will recover at least some renal function. One question, however, is how much function they recover and if this has any bearing on their overall mortality.

A paper recently published in CJASN goes a long way towards answering these questions. This was a retrospective cohort study of all 1220 patients admitted to the ICU requiring CRRT in a single center in the Netherlands between 1994 and 2010. As expected, the in-hospital mortality was high (55%). Of those who survived, 12% did not recover enough renal function to come off dialysis after discharge.

The commonest reasons for admission were thoracic surgery and sepsis. 20% of patients had pre-existing CKD, 48% had normal baseline renal function. There was no baseline in the remainder. At the time of discharge from hospital, 60% of patients had some degree of renal dysfunction (30% eGFR 30-60, 15% eGFR 15-30, 15% eGFR 0-15 including the 12% on HD). Of note, more than half of the patients with an eGFR <15 at discharge had pre-existing CKD. Unadjusted patient and renal survival is shown in the table:

The independent predictors of long term mortality were age, a surgical diagnosis, malignancy and an eGFR < 30. Similarly, the predictors of future need for dialysis were pre-existing CKD, and an eGFR < 30 at discharge. Interestingly, an eGFR between 30 and 60 was not associated with an increased risk of mortality or need for RRT in the future, relative to those with normal renal function at discharge.

This study adds to our knowledge of the predictors of outcomes after an episode of AKI requiring CRRT. No-one should be surprised that patients with significantly reduced GFR at discharge at are increased risk of mortality and need for eventual dialysis. However, it is reassuring that, in those patients who have an eGFR >60 at discharge, the likelihood of them requiring dialysis in the future is very low. It would be interesting to know if the presence of proteinuria modified the relationship between eGFR and mortality/need for dialysis, particularly in those with an eGFR between 30 and 60 at discharge but unfortunately, these data were not available.

What are you smoking?

I recently saw an interesting case series published in CJASN where they reported four cases of oliguric AKI  associated with synthetic cannabinoids use. Renal biopsy revealed acute tubular injury in three of them and calcium oxalate crystals  in two.

Interestingly, around the same period of time I was rotating in nephrology consult service and had an elderly patient with history of paraplegia and neurogenic bladder (on intermittent self-catheterization), who was brought to the ER with altered mental status for which he was intubated for airway protection. On presentation, he was found to have acute kidney injury (Cr 6.0). His renal function continued to deteriorate with no specific etiology for his renal failure, so he had a renal biopsy which showed evidence of an active tubulointerstitial nephritis with marked tubular injury and calcium oxalate crystals present within the tubular lumina. Remarkable findings in his history included the recent use of cannabinoids. He never had history of renal stones. His home medication includes: methadone, oxycodone, nortriptyline and pregabalin. Admission labs showed normal osmolar gap and negative toxicology analysis. Urine microscopy showed muddy brown casts with no identifiable crystals.  Abdominal ultrasound did not reveal any renal calculi. Renal replacement therapy was started for uremic symptoms and he continued to require replacement therapy after his discharge.

The use of these synthetic cannabinoid preparations has increased significantly in the United States over the past few years, and the incidence of acute kidney injury (AKI) from use of these agents  is underestimated. CDC investigators have identified 16 patients (15 males; median age, 18.5 years) from 6 states who presented to emergency departments in 2012 with acute kidney injury after smoking a synthetic cannabinoid product.  Six patients had acute tubular injury and three had acute interstitial nephritis. Even though we can relate tubular injury and interstitial nephritis to the use of cannabinoids  , presence of calcium oxalate crystals was perplexing. In the case series reported in CJASN, they mentioned the presence of calcium oxalate crystals in two patients, but the mechanism of development of these crystals was not fully elucidated . We are hypothesizing that synthetic cannabinoids could be the potential cause for calcium oxalate deposition in this patient (after all causes of secondary hyperoxaluria were excluded). One possible explanation is that synthetic cannabinoids contain additional compounds which are plant in origin and these may be oxalogenic

Synthetic cannabinoids use should be in our differential diagnosis for unexplained AKI in young adult population as it can cause either ATN or AIN or both. A high index of suspicion is required as they may not be detected on routine urine drug screens.

Posted by Mahmoud Kamel

Image of the Month

The renal services were consulted on a man in his late 70s with a distant history of colon cancer, recent pneumonia and NSTEMI, for investigation of worsening renal function. He had sub-nephrotic range proteinuria (2-3 g/24 hours) and an elevated creatinine (2.3 mg/dl). His serum albumin was 1.8 g/dl. Serologies revealed a negative SPEP and UPEP but a positive p-ANCA (MPO 354). His clinical condition deteriorated and he was transferred to the ICU. Notably, his urine sediment contained muddy-brown and granular casts with no dysmorphic red cells and no red cell casts.

At this point, the differential diagnosis included a vasculitis, drug-induced vasculitis (although this is usually associated with higher ANCA titers) or ATN. We proceeded to a renal biopsy.

Low power view of the biopsy specimen reveals the presence of an obvious medium-sized vessel - likely an arcuate artery

Higher power view of the cortex revealed relatively normal-appearing glomeruli with no inflammation and no crescents. There were some chronic changes with approximately 11% globally sclerosed glomeruli but this was not thought to be related to the current presentation.

There was a dense interstitial infiltrate with many plasma cells and occasional eosinophils. The small arterioles looked normal.

There were two sections of arcuate artery on the specimen:

The first section showed some arteriosclerosis and some perivascular inflammation but no vasculitis

This is a two views of the same section of a medium-sized artery. There is massive infiltration of the vessel wall characteristic of a vasculitis -specifically this has the appearance of polyarteritis nodosa. There was significant fibrin deposition on IF within the walls of the vessel. There was also some mesangial deposition of IgG and IgM.

This is a fascinating case. First, this form of vasculitis is not usually associated with a positive ANCA test and this may have been a red herring. Second, the smaller vessels were normal and if the arcuate artery was not present on the specimen, this patient would likely have been diagnosed with an interestitial nephritis. The proteinuria in this case is probably a result of reduced tubular reabsorption given the fact that there is no significant glomerular disease. The low serum albumin was most likely due to GI losses rather than renal.

Bonus History of Nephrology Point:
Although we associate interstitial nephritis with drug use and know that it was classically described in the setting of methicillin use, AIN was initially described in the setting of acute sepsis. Councilman nephritis was first described in 1898 in autopsy specimens of patients who died with sepsis. Given the plethora of drugs that most septic patients are exposed to these days prior to any biopsy, this is a difficult diagnosis to make at this point but it should be remembered that not all AIN is drugs. The image below is a plate from that paper which is available for free online.

Click on any image to enlarge

eJournal Club - Albuminuria and AKI

This month’s eJournal club concerns biomarkers of AKI. There has been considerable interest in developing novel biomarkers of AKI and CKD and a lot of effort has been focused on novel biomarkers such as NGAL, KIM-1 and IL-18. The TRIBE-AKI consortium has published a number of well-designedstudies investigating novel and traditional biomarkers. The reason that these biomarkers are desired is because creatinine elevations tend to occur relatively late in the course of AKI and therefore, the sense is that this is too late to initiate therapies which may prevent progression of AKI. However, the results of these biomarker studies have been relatively disappointing and they have not yet entered regular clinical practice.

This month in CJASN, a study was published looking at the performance of post-operative albuminuria as a biomarker of AKI in patients following cardiac surgery. The highest quintile of albuminuria was associated with a RR of 2.97 for AKI relative to the lowest quintile. While this appears good and the AUC for a model including albuminuria to predict AKI was 0.81, the majority of patients with albuminuria did not develop AKI and the model missed a significant number of patients with AKI. Still, when you combine this with other studies showing that the urinalysis is an excellent predictor of outcome in patients with AKI, older biomarkers are not looking so bad after all. Perhaps we will be able to come up with a combination of biomarkers which will allow us to better predict those patients at greater risk of AKI. To me, it seems that the bigger issue is low sensitivity rather than low specificity. I would rather have a model which will allow me to rapidly rule out those who will not develop AKI than one that will misclassify patients into a low risk group.

It was interesting in this study that ACR was not a good predictor of AKI – the absolute level of albumin performed better. This is at odds with the majority of studies which suggest that albumin should be corrected for creatinine level. This is possibly due to the large variation in creatinine generation in patients in the ICU – although relatively constant under normal circumstances, the amount of creatinine produced daily changes rapidly in sick patients – as was evidenced by a recent study of creatinine excretion in patients on CRRT.

Differentiation Syndrome

I was recently rounding on a gentleman in the ICU with acute promyelocytic leukemia (APL) who, after starting induction therapy with tretinoin (all-trans retinoic acid), developed fever, hypotension, new pulmonary infiltrates with associated respiratory failure and AKI requiring dialysis.  It was suspected that he had developed the differentiation syndrome.

Recall that APL is a variant of acute myeloid leukemia (AML).  APL is typically defined by the presence of a fusion gene linking the retinoic acid receptor alpha gene on chromosome 17 with the promyelocytic leukemia gene on chromosome 15.  Untreated, APL is the most malignant form of AML.  Luckily, it is highly responsive to therapy which usually includes tretinoin.  Tretinoin allows the terminal differentiation of malignant promyelocytes to mature neutrophils.

However, therapy with tretinoin can lead to the differentiation syndrome which was previously known (and posted about by Nate) as retinoic acid syndrome.  Symptoms include fever, edema, pulmonary infiltrates, respiratory failure, hypotension, rash, pleural and pericardial effusions, hepatic dysfunction and AKI.  The differentiation syndrome occurs in around a quarter of patients treated with tretinoin and is thought to be a cytokine release syndrome but autopsy series have also shown infiltration of various organs including the kidneys with myeloid cells.  An interesting case report in AJKD details the enlargement and subsequent return to a more normal size of the kidneys of a patient who developed the differentiation syndrome and AKI which one could speculate occurred as the parenchyma was filled then cleared of cells.

Treatment of the syndrome involves dexamethasone and in some cases holding the tretinoin.  The team caring for my patient had given him steroids and briefly held the tretinoin while providing supportive ICU care with vasopressors, mechanical ventilation and broad antibiotics while cultures were cooking. The infectious workup came back negative his overall status improved, and within a few days he was able to come off of dialysis.

Photo: Jellyfish at the Monterey Bay Aquarium.

Myeloma Cast Nephropathy: New treatment possibilities

There are a laundry list of renal complications in multiple myeloma that have been previous reviewed on RFN.  Myeloma cast nephropathy is one of the most frequent, being found in approximately a third of patients in autopsy series.  Acute kidney injury is a common presentation of myeloma cast nephropathy with a variable amount of proteinuria.  As a tubular interstitial lesion with intact filtration barrier lower levels of albuminuria are typically present however large amounts of serum free light chains can be present leading to the classic findings of a negative urine dipstick (which detects albumin) with high levels of proteinuria by quantitative evaluation (stay frosty medical students, your intern is just itching to pimp you on this one).

On light microscopy diffuse tubular damage resembling ATN is seen along with distinctive distal tubular casts (in contrast to light chain fanconi syndrome where intracellular proximal tubular deposits are seen).  These casts often have sharp edges, a tendency to fracture (image on the left) and frequently have adherent neutrophils, monocytes or multinucleated giant cells around their periphery (image on the right).

Two papers from a group in Alabama shed light on the mechanism of formation of these casts and new potential treatment strategies.  It has long been known that the casts are composed of light chains bound to Tamm-Horsfall protein.  What the group first showed is that the CDR3 region on free light chains is the critical determinant of the binding with Tamm-Horsfall protein.

In their more recent paper, they report the development of a competitive inhibitor of the light chain Tamm-Horsfall protein interaction by blocking the Tamm-Horsfall protein binding site.  In a rodent model, in which human serum from patients with multiple myeloma was used to induce myeloma cast nephropathy they demonstrate the ability of the inhibitor to prevent both the histologic changes of myeloma cast nephropathy as well as AKI.

The inhibitor was infused just four hours after the serum containing light chains so future studies will need to examine situations that more closely mimic human disease in which presentation to care is delayed for much longer periods of time.  Despite this, the study adds to our understanding of the mechanisms on AKI in patients with myeloma casts nephropathy and provides a new avenue for investigation of treatment of renal disease in patients with myeloma casts nephropathy independent of chemotherapy.

Images from the recent NephSap Pathology edition.

Mercury rising

A patient who had been working in a recycling company that handled thermometers presented with fever, dry cough, fatigue and rash. Based on imaging (CXR showed massive radio-opaque material in the lungs, right atrium and right ventricle; skeletal survey showed radio-opaque deposits in the kidneys, bowel wall, and bladder wall), symptoms, and a positive history of exposure, a diagnosis of mercury intoxication was made. The patient developed multi-organ failure including anuric acute renal failure, and nephrology was consulted. Further background details on the case can be found here. What is the treatment and the role of dialysis in mercury intoxication? 


Metallic mercury has a widespread use both within industry and in many everyday objects such as thermometers, dental amalgams, batteries, fluorescent light bulbs, and many others. Mercury intoxication can result from vapor inhalation, resulting in severe respiratory symptoms, or from injection, usually in cases of attempted suicide. 


The chelating agents 2,3- dimercaptopropanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are central to the management of mercury toxicity. DMSA is given orally, and can cause leucopenia and elevated liver enzymes. DMPS is an intravenous medication and its use is associated with hypotension. In our patient, DMSA 500 mg po q 8hrs was given for 4 days, before it was discontinued because of elevated LFTs and leucopenia. We then started DMPS with CRRT but unfortunately, after two weeks of supportive treatment, the patient died. 


Chelators such as DMPS and DMSA work by mobilizing mercury and facilitating its excretion through the kidneys. This creates a management conundrum in the anuric patient, as this route of excretion is not available. Consistent with this, our patient’s blood mercury levels rose dramatically during chelator treatment, despite CRRT. We hypothesize that the administration of DMPS mobilized mercury from extracellular deposits and redistributed it to the blood and organs, but it failed to be adequately eliminated from the body because of anuria. For this reason, intensive CRRT with a high-flux dialyzer is a critical adjunct to chelator therapy. If this is not available, continuous renal replacement therapy with chelators have showed better mercury clearance than conventional dialysis, whereas peritoneal dialysis has been shown to be ineffective at clearing mercury. These principles should be borne in mind in other heavy metal poisonings also. Other management pearls I took from this unusual case were to initiate dialysis early and to give DMSA at a lower and more frequent dose to avoid serious side effects. 


Tarek Alhamad M.D.

The ABCs of ADME in AKI

The pharmacokinetics of a drug refers to the study of the absorption, distribution, metabolism and elimination of that drug (often referred to as ADME). Each of these characteristics can be greatly altered in a patient presenting with acute kidney injury (AKI). Historically, dosing in AKI has not been distinguished from that of chronic renal insufficiency (CRI). Newer evidence suggests that pharmacokinetic alterations differ between AKI and CRI, and; therefore, dose adjustments may also be different.

Absorption

The bioavailability of a drug can be influenced by GI transit time, gastric pH, and intestinal drug metabolism. Gastric pH can be increased in patients presenting with AKI, which may decrease dissolution and ionization of the oral drug and lead to reduced absorption. In CRI, intestinal metabolism can be reduced potentially resulting in increased absorption. The effect of AKI on intestinal metabolism has not been well-studied.

Distribution

Drug distribution is dictated by many factors, one of which is a medication’s ability to bind to plasma proteins, such as albumin. Patients with AKI may present with low serum albumin levels, leading to a higher free-fraction of albumin-bound drugs (e.g. warfarin, phenytoin, valproic acid, and salicylates) and consequently, increased biological effect.

Other factors affecting drug distribution include serum pH and fluid status. AKI is frequently associated with acidosis, which may affect the ionization and ultimately the distribution of the drug into the tissues. Lastly, increase in fluid volume in the blood can lead to low drug concentrations.

Metabolism

Many drugs undergo metabolism prior to elimination. A myriad of co-morbid conditions frequently associated with AKI may affect drug metabolism such as liver and cardiac dysfunction. Non-renal clearance can be decreased in the setting of CRI, possibly due to a chronic accumulation of uremic by-products causing an impairment of drug metabolic enzymes. As this is a chronic process, the same may not hold true in the early stages of AKI.

Elimination

AKI may have opposite effects on drug elimination. While significant nephrotic syndrome may increase the clearence rate of large molecules and highly protein-bound drugs, acids and bases may accumulate in AKI and compete for transporters, thus diminishing tubular secretion of drugs eliminated by anionic and cationic transport systems.

In sum, the pathophysiologic process in AKI is different from that of chronic CRI, and the pharmacokinetic parameters of medications may differ in the two disease states. Therefore, drug dosing principles studies in CRI may not hold true for patients presenting with AKI, and further research will be necessary to ensure proper dosing of medications in AKI and better guide us in our daily clinical decisions.

Craig A. Stevens PharmD, PGY1 Pharmacy Practice Resident

Steven Gabardi PharmD, BCPS, Organ Transplant Clinical Specialist at BWH

References

Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 2001;40:159-68.
Klotz U. Pathophysiological and disease-induced changes in drug distribution volume: pharmacokinetic implications. Clin Pharmacokinet 1976;1:204-18.
Power BM, Forbes AM, van Heerden PV, Ilett KF. Pharmacokinetics of drugs used in critically ill adults. Clin Pharmacokinet 1998;34:25-56.