Epstein Barr Virus & Acute Interstitial Nephritis

Acute interstitial nephritis (AIN) has resurfaced as an important cause of kidney injury in the hospitalized patient, particularly because of recent evidence implicating such common medications as proton pump inhibitors. Though most current cases of AIN have been attributed to medications and autoimmune disorders, a patient I recently encountered on the consult service reminded me of an additional cause.

The patient in question was a woman with rapidly-progressive, oliguric, acute renal failure. She had just been hospitalized with infectious mononucleosis and her Epstein Barr Virus (EBV) DNA viral load was >11,000 copies/mL. Her symptoms resolved with intravenous hydration, and she was discharged in two days. Unfortunately, the patient returned two weeks later with fevers, flank pain, and anorexia. Her exam was normal apart from mild edema. Urinalysis revealed 100 mg protein, trace ketones, 21 white blood cells, and three red blood cells. A urine protein/creatinine ratio was 0.62. Serum creatinine was 2.58 mg/dL, total CO2 was 14 mmol/L, and she had no peripheral eosinophilia. The patient was initially treated with hydration and antibiotics for presumed pyelonephritis. When a urine culture revealed no organisms and her renal function continued to deteriorate, Nephrology was consulted.

Our differential diagnoses included pre-renal azotemia, acute tubular necrosis from sepsis or hypoperfusion, post-infectious glomerulonephritis, and AIN. My sediment analysis only revealed a few granular casts. Given the patient’s normal renal function at baseline, absence of diuretic use, and oliguria, we interpreted her fractional excretion of 1.1% to indicate intrinsic renal pathology. A renal ultrasound revealed mildly enlarged kidneys with increased echogenicity. Serum complements as well as anti-nuclear and anti-neutrophil cytoplasmic antibody levels were all normal. Her EBV DNA viral load was now 220 copies/mL. The patient’s creatinine continued to rise in spite of adequate hydration and discontinuation of nephrotoxic agents, peaking at 4.04 mg/dL. By this time, she was found to have an elevated urinary eosinophil count. Despite having a positive predictive value for AIN of only 30%, the patient’s urinary eosinophils increased our post-test probability for AIN in this clinical situation. As she had no comorbidities, took no home medications, and had only received antibiotics for a few days, Epstein-Barr Virus (EBV) was presumed to be the cause.

Our patient was hesitant to undergo a renal biopsy, and as the potential benefit of corticosteroids outweighed any risks, she was empirically started on 1 mg/kg po prednisone daily. Her renal function began to improve the following day and was ultimately restored to premorbid levels at her two-week follow-up visit.

Though viral infections have long been described in textbooks as known causes of AIN, few case reports of it exist in the current literature. EBV-associated AIN was first reported in 2000 when a 17-year old patient presented with jaundice, hemolytic anemia, and acute renal failure. Serology revealed elevated EBV IgM and IgG viral capsid antibody titers, elevated IgG early antigen titers, and negative IgG nuclear antigen titers. Renal biopsy and subsequent light microscopy revealed a patchy, interstitial infiltrate comprised of lymphocytes, plasma cells, eosinophils, and neutrophils. In-situ hybridization for EBV mRNA was positive. Serum creatinine returned to normal one month after treatment with prednisone. Other cases were published with similar presentations and outcomes, but reports of EBV-associated AIN continue to be scarce.

Two competing theories exist which seek to explain the pathogenesis of EBV-associated interstitial nephritis. One suggests that kidney injury is simply collateral damage from activated T lymphocytes responding to the infection. Another theory indicates that direct toxicity from the virus itself plays a role. Is EBV-associated AIN then, a result of direct viral infection or is it a consequence of an immunologic response? The literature is conflicting. Biopsied cases of EBV-associated interstitial nephritis do reveal a predominance of cytotoxic T cells. However, Mayer et al failed to identify EBV RNA in renal biopsy tissue and instead suggested that the EBV antigens in infiltrating lymphocytes activated a massive T-cell mediated immune response. This was demonstrated once more in a 2011 study that detected no EBV DNA in renal biopsy specimens of patients with suspected AIN.

In contrast, both Bao’s and Cataudella’s analyses reported the detection of the EBV genome using polymerase chain reaction (PCR) techniques in renal biopsy samples. However, EBV DNA has since been inconsistently found in other renal biopsy specimens, and EBV DNA has been found in biopsies of patients with IgA Nephropathy and Membranous Nephropathy as well.

EBV’s direct role in infection is less debated in patients with chronic interstitial nephritis. Becker et al used in-situ hybridization and PCR techniques to show that renal biopsies of patients with “idiopathic” chronic interstitial nephritis actually had EBV genomes expressed in their proximal tubule epithelia. It is now known that asymptomatic EBV can persist within B lymphocytes and that reactivation can result in a robust, pro-inflammatory cytokine cascade.

Without more invasive testing, it is impossible to determine whether our patient’s acute renal failure was a result of the virus’s direct nephrotoxicity as opposed to a consequence of cytokine-mediated inflammation. Though she was not prescribed any antiviral agents, these are not routinely recommended in immunocompetent persons infected with EBV. In the same vein, we cannot assume her rapid improvement with corticosteroids supports the pro-inflammatory hypothesis of EBV-associated AIN.

Further studies analyzing the presence or absence of EBV DNA in patients with both AIN and chronic interstitial nephritis are needed. Such studies may provide basis for the use of corticosteroids, determine baseline characteristics of latent EBV, and help to develop our understanding of the pathogenesis of AIN in general. Cases like that of our patient’s also serve to remind us of less common causes of AIN to bear in mind when in clinic or on the wards.

 Posted by Devika Nair, Vanderbilt Nephrology Fellow

False-positive AKI and the perfectly imperfect biomarker

A small absolute change in serum creatinine level, 0.3 mg/dl, is used by Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines to define the presence of Acute Kidney Injury (AKI). The base of this definition was formed by several studies findings of strong association between adverse outcomes and minor changes in serum creatinine level. Subsequently, evidence emerged suggesting that this may not be true to the same extent in people with pre-existing CKD, because variations in serum creatinine concentration are common in these individuals.

As with all other laboratory tests, serum creatinine measurements are affected by within- and between-sample coefficients of variation, intra-individual variation and biologic variation. Biological variation may result from variations in diet, muscle mass and breakdown, tubular secretion, variability in volume homeostasis and from medications uses. The variation in measured serum creatinine level could be as high as 9%. Because only a small increase in serum creatinine is needed to meet AKI criteria, random variation in creatinine level may be a significant contributor to AKI diagnosis in the absence of a true reduction in GFR. This is called a false-positive AKI. It has been shown that high variation in serum creatinine in the period, of days, preceding the development of AKI was not associated with the anticipated inpatient mortality or dialysis. This observation supports the existence of false-positive AKI.

Lin et al demonstrated, using the KDIGO definition, an 8% overall false-positive rate for AKI diagnosis. This rate was much higher, 31%, for the subgroup of CKD patients with serum creatinine ≥1.5 mg/dl. Therefore, an absolute change in serum creatinine of 0.3 mg/dl may represent a relative inconsequential change in GFR in CKD patients rather than a superimposed acute injury.

In my opinion, false-positive AKI could largely explain why most randomized trials for early intervention in AKI have been unsuccessful in improving outcomes. AKI is misclassified under frameworks that do not reflect true GFR reduction. Consequently, patients with false-positive AKI are included in AKI studies and dilute observed effect sizes. This potentially leads to false-conclusions that certain interventions are ineffective and do not improve outcomes. The underlying severe disease is quite likely the actual mediator of adverse outcomes seen in AKI. Therefore, small changes in serum creatinine may be nothing more than a reflection of the severity of the underlying disease process. This point remains a topic of hot debate. Moreover, AKI definition using small increments in serum creatinine level has not been validated among patients with CKD.

It is obvious now that serum creatinine is an imperfect AKI biomarker; especially that it is being used on the basis of a relative change in value of a continuous variable instead of the crossing of a particular threshold. The ideal biomarker would accurately detect true reduction in GFR, be detectable early in the course of renal dysfunction to allow for timely intervention, and predict outcomes. It is likely that current AKI criteria will eventually be modified at least in part by sensitive and specific biomarkers of kidney injury. The use of such biomarkers will help in the development of a new paradigm for classifying AKI that is not only dependent upon serum creatinine. Meanwhile, the awareness about false-positive AKI should be highlighted and the limitations of serum creatinine, as an AKI biomarker, should be re-emphasized.

Authored by Mohammed A. Kaballo, Nephrology Fellow, Ireland

Lazarus Kidney

For my inaugural RFN post, a special case I saw last year with Dr. David Mount and Young-Soo Song a fellow nephrologist in training at BMC. 

A 74-year-old man with history of HTN, peripheral artery disease, CKD (baseline Cr 1.6) who initially presented with NSTEMI. He was placed with a balloon pump (IABP), and underwent CABG on Day 2. Post-operatively he was quickly weaned off pressors. On Day 3, the IABP was removed. He suddenly became anuric. His creatinine increased from 2.0 on Day 2 to 3.17. 

 He was evaluated for the differential of anuric AKI, we had a high suspicion for renal artery occlusion, due to the relation to the retrieval of the IABP. Angiography confirmed complete occlusion of the renal arteries. Attempts at IR-thrombectomy failed, the renal arteries were bluntly occluded at the level of the aorta. 

We decided to pursue revascularization despite some doubts from surgery. He underwent a Hepato-right renal artery bypass on day 7 (4 days after the insult). He was off dialysis, urinating freely with decreasing creatinine in less than a week. 

Clues that revascularization was going to be successful: 

- On renal ultrasound the right kidney was 10.8 cm with normal echotexture. But the left kidney was 8.79 cm with cortical thinning suggesting a chronic renovascular disease. 

 - The MAG-3 scan showed persistent perfusion of the right kidney From experimental models of renal ischemia, we know that there’s irrevocable destruction of the kidney, within hours of loss of perfusion (Sanchez Fructuoso, JASN 2000; Hamilton PB, Am J Physiol. 1948). However, there’s a minimal perfusion pressure that is capable of maintaining nephron viability without sustaining filtration (Moyer, Annals Surg 1957). 

Renal perfusion is not only via the renal artery. There are small preformed collaterals that originate from the lumbar, internal iliac, gonadal, adrenal, renal capsular, intercostal, and mesenteric arteries. They can drain into the distal part of the renal artery or provide direct cortical perfusion (Love L, et al. Am J Roentgen 1968 and Lohse JR, Archives of Surgery 1982). Renal ischemia provides a maximal stimulus for vasodilatation of these collaterals. 

 In the case of our patient, his right kidney likely had sub-clinical renovascular disease that led to development of these collaterals. On occlusion of the renal artery he had sufficient collateral perfusion to maintain enough nephron viability to get off dialysis.

 In this table are a few examples that show how long these collaterals can maintain viability. 

Time To revascularization	Injury	Citation
6 days	Endovascular aneurysm repair	Hamish M Journal of Endovascular Therapy 2010
3 months on HD	Atherosclerotic	Simeoni S, Eur J Vasc Endovasc Surg 2004
6 months on HD	Occlusion of solitary kidney artery graft	Cohen DL, Townsend RR, Am J Kidney Dis 2001

 As per Dr. Cohen and Townsend’s discussion in 2001, proposed criteria to consider revascularization of the renal artery include:
-Patent distal main renal artery or the identification of collaterals. It’s important to notify the interventionalist that we’re looking for that, a routine angio will not pick that up easily.
-Biopsy evidence of viable glomeruli in a representative specimen.
-Renal size greater than 9 cm
-Evidence of perfusion either by MAG-3 scan (debatable) or Renal Doppler

Charbel C. Khoury

Scleritis and Kidney Disease - More than meets the eye...

Scleritis is a severe inflammation involving the deep episclera and sclera. Symptoms include moderate to marked pain, hyperemia of the globe, lacrimation, and photophobia.

Scleritis tends to recur and is frequently associated with an underlying systemic illness, such as rheumatoid arthritis, lupus, IgA vasculitis, polyarteritis nodosa and granulomatosis with polyangiitis.   A few cases are infectious in origin and about half of the cases of scleritis have no known cause.

 In Renal Grand Rounds on Tuesday, Patrick McGlynn presented a case of 30 year-old healthy female who came to clinic complaining of pain and redness on her right eye. Blood pressure was elevated at 155/90 mmHg. On exam, right eye had redness on sclera. No involvement of left eye. No papilledema on fundoycopic exam. Ophthalmology was consulted and thought the exam was consistent with sectoral scleritis inferotemporally on right eye (representative figure above). Labs showed a creatinine of 1.79mg/dL and urine sediment analysis revealed few WBC casts. Based on acute presentation with renal failure and active urine sediment, a kidney biopsy was performed, revealing IgA nephropathy.

 Ocular involvement in patients with IgA nephropathy is infrequent, but may lead to uveitis, episcleritis, scleritis or retinal vasculitis. For sure worth keeping an eye…

NephroCheck®—can we predict AKI in the ICU? And then what?

Nephrologists have been looking for sensitive biomarkers to predict AKI. Efforts have been made and the idea of “renal angina” was proposed by Goldstein and Chawla in 2010, but still there has been no reliable biomarker commercially available to detect AKI early enough. 
Well, the FDA has just approved a point-of-care biomarker assay, NephroCheck®, for predicting risk of AKI. Interestingly, none of the most studied biomarkers such as KIM1 and NGAL are included. NephroCheck® uses two urinary biomarkers : insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases (TIMP-2).

IGFBP7 and TIMP-2 were selected as biomarkers to predict AKI using a 522-patient cohort (median age 64, 91% Caucasian) of critically ill patients admitted with sepsis, shock, major surgery and trauma—though inclusion criteria differed based on the facilities (Crit Care 2013). Over 340 biomarkers were screened, including urine kidney injury molecule-1 (KIM-1), plasma and urine neutrophil gelatinase-associated lipocalin (NGAL), plasma cystatin-C, urine interleukin-18 (IL-18), urine pi-glutathione S-transferase (pi-GST) and urine liver fatty acid-binding protein (LFABP).

IGFBP7 and TIMP-2 are both inducers of G1 cell cycle arrest and showed the highest AUCs on the above cohort (0.76 and 0.79 respectively, and 0.80 when combined). The results were then validated using another 722-patient cohort, without evidence of AKI on admission. Primary outcome was AKI stage 2-3 (KDIGO) within 12-18 hours post-test. There was also another validation study published earlier this year (AJRCCM 2014), using 420 patient from 23 facilities in the US, demonstrating sensitivity of 92% (95% CI 85-98), and specificity of 46% (95% CI 41-52) with cut-off value of 0.3 (ng/ml)2/1000. AUC was 0.82 (0.76-0.88).

Although NephroCheck may have potential advantage to rapid response to developing AKI, still there is substantial limitations of the study including: heterogeneity of the validating cohorts, Caucasian racial predominance, focusing on septic AKI and reflecting more ischemic/hemodynamic-related AKI/ATN.
 So, what should we do next, based on the early detection/ risk prediction of AKI? What interventions or drugs could we use to prevent AKI development in those high-risk patients? Specific treatment strategies for AKI are now warranted for this biomarker to be in full use in the fight against AKI.
Figure from Crit Care 2013 paper: Proposed mechanistic involvement of the novel biomarkers in AKI.

Naoka Murakami

Hyperammonemia - When should we start dialysis?

I would like to discuss a case that I recently saw in renal consult. He was a man in his 60s with history of end stage liver disease who received a liver transplant. His hospital course was complicated by anuric ATN and liver graft failure. As a result, he was started on dialysis on post-operative day 0.  Dialysis was stopped on post-op day 2 due to recovering renal function. On post-op day 3 he became encephalopathic. His ammonia level was elevated to 337 and did not improve with conventional therapy with lactulose/rifaximin. The question was whether to start dialysis or not in spite of his recovering renal function.

Causes: The urea cycle in the liver in which ammonia gets converted to urea is responsible for excretion of waste nitrogen.  Hyperammonemia in newborns is most commonly associated with inherited disorders of amino acid and organic acid metabolism. Causes in adults include Reye’s syndrome, liver failure, sepsis especially infections with urea splitting organisms, high dose chemotherapy, drugs (salicyclates, valproate), gastrointestinal bleeding, multiple myeloma, parenteral nutrition and late onset of urea cycle defects. The latter usually presents with episodic encephalopathy precipitated by metabolic stressors like infection, anesthesia or pregnancy.

Clinical features: Hyperammonemia can be life threatening and if persistent can lead to irreversible neuronal damage. It leads to cerebral edema causing progressive encephalopathy. Respiratory alkalosis is common due to central hyperventilation. Severe hyperammonemia can also cause seizures. An MRI brain is usually consistent with hypoxic ischemic encephalopathy

When to start dialysis? There are no published guidelines for when to initiate dialysis in a patient with hyperammonemia due to urea cycle defects. It is commonly indicated if the ammonia blood level is greater than three to four times the upper limit of normal or greater than 200 micromoles/L. Continuous hemodialysis is started with higher flow rates and is the most effective treatment in rapidly reducing ammonia levels.  Even though ammonia is osmotically active, the rapid removal of ammonia is not associated with disequilibrium syndrome mainly due to two reasons: First, there is a rapid equilibration of ammonia across the cell membrane. Secondly, the total amount in the blood, even in severe hyperammonemia, is only about 200 micromoles. This contributes less than 1 mosm per liter to total osmolality and therefore, even if it were all removed at once, the change in osmolality is too small to make cause disequilibrium. Contrast this with ammonia levels in the urine which are typically in the millimolar range.

The question remains whether to start dialysis in the setting of acute severe hyperammonemia (levels > 200 micromoles/L) and encephalopathy in adults with liver failure and normal kidney function. I was not able to find any literature on it and would like to know what the practice in other institutions is?  I believe since severe hyperammonemia can lead to irreversible brain damage, dialysis should be instituted. See this previous post concerning hyperammonemia in individuals with myeloma.

Posted by Silvi Shah

Tick borne diseases for the nephrologist - Babesiosis

The following few posts are a summary of tick borne illnesses that can cause renal failure and/or electrolyte problems. 

Babesiosis

First identified on Nantucket Island in 1969 and was initially know as Nantucket fever.

Endemic areas.
CDC map. Reported cases in 2012

Cases have been reported in Europe (Croatia, France, Great Britain, Ireland, Portugal, Spain, Sweden, Switzerland)(Babesia divergens).

The tick.

Ixodes scapularis. The Blacklegged tick.

The pathogen.

Babesia microti and B. duncani (USA). B divergens (Europe). Protozoan parasites infecting red blood cells

Humans are not a natural host. Infection by blood transfusion has been reported.

Incubation period 1 – 9 weeks

Clinical features.

Fever, chills, sweats, Malaise, fatigue, Myalgia, arthralgia, headache, Gastrointestinal symptoms, such as anorexia and nausea (less common: abdominal pain, vomiting)

Dark urine

Less common: cough, sore throat, emotional lability, depression, photophobia, conjunctival injection

Mild splenomegaly, mild hepatomegaly, or jaundice may occur in some patients

Lab features

Haemolytic anemia, thrombocytopenia, renal failure, transaminitis.

Diagnosis - Light microscopy of blood cells, serology and PCR for B. microti or B. duncani

Treatment - Atovaquone plus azithromycin or quinine plus clindamycin orally for 7 to 10 days.

Atovaquone plus azithromycin is preferred as this combination is better tolerated.

The source for this review is mainly from the CDC website as well as various references cited in the posts. The tick pictures provided may differ from what might be found on a bitten human. Ticks become larger and engorged after feeding and will look different.

The Lone Star Tick

Recently a 65-year-old female was referred to an ED in the state of Missouri complaining of fevers, chills, headache, diarrhea and vomiting occurring over the last week. 3 weeks prior she had received an orthotopic liver transplant. Her post transplant course was unremarkable and she was discharged on prograf 2mf bid, myfortic 360mg bid, prednisone tapering, Bactrim single strength daily and valcyte 450mg od. She also took thyroid replacement, Januvia, warfarin and aspirin. Past medical history included diabetes, heart failure, dysfunctional uterine bleeding, hypothyroid and PUD. She also had CKD with a creatinine about 1.4mg/dl. On examination her Temp was 38.6, HR 110, BP 113/76 and O2sats 99% on RA. She had no nuchal rigidity but reported a sore neck. She had an erythematous area on her lower back. The rest of her exam was normal.

Her initial labs were:

Hb 6.3, WCC 2.7 (94%neuts, 5.8%lymphs), platelets 35

NA 122, K 5.6, Cl 100, CO2 11, BUN36, Creat 2.3, Gluc 173

Arterial pH 7.31, CO2 20, O2 102

AST 52, ALT 41, AP 155, GGT 171, Bili 0.6, Alb 3.3

UA, No blood, 1+protein, 2 rbc, 2 wbc

She had a normal CT brain and was started on multiple antibiotics in the ED.

On further questioning her daughter reported removing a tick from her back after the patient went out looking at deer close to her house.

Lets pretend the daughter brought in a picture of the tick (see above)!

Lab trends; admission to discharge.

Hb 6.3

WCC 2.7                   1.4           0.6           0.5           0.3           1.2           2.4

94%neut                90            91            87            83            60            59

5.8%lym                 6               6.7           9.2           14            16            28

plt 35                       16            18            24            28            26            31

NA 122                    128         132         135

K 5.6                   

Cl 100

Co2 11

BUN36

Creat 2.3                 2.2           1.8           1.6                                               1.3

Gluc 173

pH 7.31

CO2 20

O2 102

AST 52                                                                                                               31

ALT 41                                                                                                               31

AP 155                                                                                                              249

GGT 171                                                                                                                            

Bili 0.6                                                                                                               0.8

Alb 3.3

UA

No blood

2 rbc

2 wbc

1+protein

No lumbar puncture was performed.

To summarize, this lady had constitutional symptoms, fever, neurological symptoms, GI symptoms with a rash and a tick bite. She had pancytopenia, transaminitis, hyponatreamia and renal failure.

Her antiproliferative medication and anti-infective medications were held (Myfortic, valcyte and Bactrim).

IV Doxycycline was commenced.

Sodium and creatinine improved and potassium became low, likely due to GI losses.

Interestingly her leucopenia followed the classical pattern of lymphopenia followed by leucopenia and she required G-CSF. Her transaminases were normal at the time of discharge.

Diagnosis = Ehrlichiosis 

The first case of human ehrlichiosis was described in 1986.

The two most important species to infect humans are Ehrlichia chaffeensis which causes human monocytic ehrlichiosis (HME) and Anaplasma phagocytophilum which causes human granulocytic anaplasmosis (HGA). Both of these diseases have the same vector and have very similar clinical and laboratory features. Ehrlichia ewingii is a less common cause of ehrlichiosis than Ehrlichia chaffeensis.

Ehrlichiae are obligate intracellular bacteria found in membrane bound vacuoles in human and animal leukocytes.

The most endemic area is the southeastern USA – ‘the tick belt’. See the CDC map for the endemic regions in the USA. Cases have also been reported in Europe, Africa, South America and Mexico.

The lone star tick (Amblyomma americanum) is recognized by the CDC as the principal vector of Ehrlichia chaffeensis and Ehrlichia ewingii in the U.S.; both disease agents are responsible for causing ehrlichiosis in humans. White-tailed deer are a primary host of the lone star tick and appear to serve as a natural reservoir for E. chaffeensis. The lone star tick is also a vector of Francisella tularensis, causal agent of tularemia. Adult ticks parasistize deer, cattle, horses, feral swine, sheep, dogs, and humans.

Most infections occur in the spring and summer in the USA.

The clinical manifestations in the elderly and immunosuppressed can be very severe but the following are the usual clinical features:

Fever - Some fevers can be protracted over weeks

Malaise, myalgia, headache and chills – 2/3

Nausea, vomiting and arthralgia – ¼ to ½

Rash (Macular, mucopapular, petechial) – 1/3

Meningism – ¼

More rarely – Seizures, coma, renal failure, heart failure and respiratory failure

There has been a single case of myocarditis and multi-organ failure in a healthy adolescent.

Laboratory findings:

  

Most common triad is leucopenia, thrombocytopenia and elevated transaminases.

CBC

Leucopenia. This tends to be caused by lymphopenia initially followed by neutropenia as in this patient.

Thrombocytopenia

Anaemia

CHEMISTRY.

Elevated transaminases, LDH and Alk phos

Hyponatreamia

Elevated creatinine

CSF, when neurological symptoms

Lymphocytic pleocytosis and elevated CSF protein

Diagnosis

Usually by PCR methods. Note this test may not detect the recently reported third species, E. muris, found in Wisconsin and Minnesota.

Differential diagnosis

This can be a difficult diagnosis to make. It is clinically and geographically similar to RMSF. It can also present like mononucleosis, TTP, hematologic malignancy, cholangitis, the early phases of hepatitis A infection. This is especially so in immunocompromised patients whose clinical features may not be as obvious initially. Common transplant drugs such as Bactrim/Septra, valganciclovir, mycophenolate and azathioprine can also cause cytopenias.

Treatment (adults)

Doxycycline 100mg iv or po bid for about 10 days.

Note this will also treat RMSF which is often confused with ehrlichiosis.

Outcomes. Mortality is about 5%. Most commonly due to viral or fungal super-infections (Invasive aspergillosis, candida, HSV).

This interesting case illustrates the difficulty in diagnosing tick borne infections. They can be lethal and severe in our immunosuppressed transplant population and can be a cause of renal failure in any patient. Also of interest in this case is the lymphocytopenic and neutropenic trending that is usually more peculiar to Anaplasma phagocytophilum which causes human granulocytic anaplasmosis (HGA). We did not test for A phagocytophilum as ehrlichae PCR was positive.