Infections and intravenous iron

An interesting study appeared in my email this morning examining the association between the use of iv iron and outcomes in hemodialysis patients with systemic infections. Current guidelines from all of the major societies suggest that if patients are admitted with bacterial infections in particular, iv iron should be stopped. There are both basic and clinical data supporting this recommendation although it should be said that the evidence is weaker than one would imagine.

The biologic plausibility argument rests on the fact that high iron concentrations have two negative effects in the context of infection. First, iron appears to impair the function of both neutrophils and T-cells. Patients on dialysis with iron overload have been shown to have reduced neutrophil function and phagocytosis. Similarly, impaired PMN function has been seen when neutrophils from healthy controls are incubated with ferric compounds. However, it should be pointed out that iron is vital for normal neutrophil function and individuals with iron deficiency also have impaired function. Clearly there is a sweet spot for neutrophil function but we are uncertain what it might be.

The evidence for a clinical effect for iron infusions on increasing infection frequency and severity is based on two separate strands (well summarized here). First, multiple observational studies have shown that high ferritin levels (particularly when >1000) are associated with an increased frequency of bacterial infections. There are clear limitations here. First, this finding is not consistent across all studies (4 of 14 studies did not find this association). Second, ferritin is an acute phase reactant itself and is not necessarily always elevated due to iron overload. Third, most of these studies were done in the pre-ESA era where much of this iron overload may have been due to transfusions. Finally, all of these studies were observational. As such, it is impossible to say if the risk of infection may not have been due to other factors which also lead to a higher iron requirement/ferritin levels.

The second strand of evidence is observational studies showing that higher doses or frequency of iron infusions are associated with a higher risk of future infection. Again, all of these studies are observational and so the same criticism as above applies. Similarly, there is a lack of consistent results across all studies although it should be said that the largest studies with the most patients did find an effect. However, in the most recent large study of ~120,000 medicare patients, while there was an increase in the risk of infection with higher doses of iron, the HR for infection for high vs. low dose was only 1.05. None of these studies examined the effect of ongoing iron administration on the severity of infection in dialysis patients. One could say that they are an argument against using iron in dialysis patients (which is not realistic) rather than arguments for stopping during an infection.

Today's email is thus especially welcome. This is a study published in CJASN which examines the relationship between ongoing iron use and severity of infection in Medicare patients. In total, 22,820 individual who had received iv iron in the 14 days prior to admission with a bacterial infection were included. 10% of these patients also received the iron while they were inpatients or shortly afterwards and were included as the cases. The controls were individuals who did not receive iron (i.e the iron was stopped per guidelines). The receipt of iv iron was not associated with increased short or long term mortality, LOS or likelihood of readmission in the next 30 days.

What is the explanation for this finding? One important question is why those 10% of patients did not stop iv iron after admission despite the clear consensus suggesting that it should be done? Looking at the table of demographic and clinical characteristics, there was nothing sticking out that suggested a reason for this difference and there may have been unmeasured characteristics that explained the difference. The outcomes were hard (as they would have to be given the source of the data) but may miss some subtle differences in outcomes related to the infection itself. That said, mortality and readmission are probably the most important outcomes. Finally, again this study was observational and needs to be interpreted as such.

All that said, this is an excellent addition to the literature which raises many more questions that it answers. These are important questions - too much of what we do in nephrology is based on consensus rather than clinical trials. Perhaps this might stimulate someone to do the necessary trial to answer this question once and for all.

Gearoid McMahon

Preventing PD Peritonitis: What's the Evidence?

Peritoneal dialysis associated peritonitis is the second commonest cause of death among PD patients (35/1000 years) and the most common cause of treatment failure. It confers a CV risk of 7 times normal for 6 months following the bacteremia, so we need to remain ever vigilant when dealing with PD patient, and its worth refreshing our knowledge on how to prevent this feared complication. There is a paucity of high quality evidence for many of the most fundamental questions in PD. Such is the lack of evidence, the International Society for Peritoneal Dialysis (ISPD) have issued a consensus document where they state they are unable to issue formal guidelines.

The best resources I have found on the topic are a Kidney International supplement from 2006, and the ISPD document already mentioned. In the first instance, which patients are at risk of developing peritonitis? The best described risk factors are hypoalbuminemia (similar to the association in haemodialysis patients), Staph aureus  carriage at inception of dialysis (HR 1.53), initiation of PD early after catheter insertion (HR 0.98/day), PD after transplant failure (HR 2.18), lower hemoglobin (HR 0.88/gram/l), faster PD transport rates (HR 2.92) and previous peritonitis. A special risk group to consider are those PD patients undergoing invasive procedures such as endoscopy or IUD insertion. There is evidence that antibiotic prophylaxis using cephalosporins may help reduce peritonitis rates.

The cornerstone of peritonitis prevention is minimizing contamination risk with effective hand washing and immaculate exchange technique. Specialized nurse-led training is key. If peritonitis occurs, retraining and re-education are the most important interventions. Home visits by PD nurses can cut recurrence rates in half, and should be performed where possible. A Cochrane review could find no RCT data to support any particular insertion technique, catheter type, number of cuffs or positioning. It demonstrated that of all catheter-related interventions designed to prevent peritonitis in PD, only disconnect (twin-bag and Y-set) systems have been proved to be effective. Topical antibiotic prophylaxis is a standard of care and there are multiple RCTs demonstrating the efficacy of mupirocin cream application at the exit site. Ointment is to be avoided as it can erode the catheter polymer.  In contrast, nasal mupirocin is more difficult to justify. Cochrane point out that while there is trial data that nasal mupirocin reduces exit-site/tunnel infection, it has no effect on peritonitis rates. Preoperative intravenous prophylaxis reduces early peritonitis but not exit-site/tunnel infection. 

Recent published trials in the area of antimicrobial prophylaxis have been disappointing. They include the Honeypot study, discussed previously on RFN, which demonstrated the application of honey to exit sites approximately doubled the risk of developing peritonitis in diabetic patients. The MP3 study published in JASN in 2012 found polysporin to increase rates of fungal exit site infections without any improvement in primary outcomes of exit site infection or peritonitis. Finally, a special mention goes to cats, who are responsible for at least 25 case reports of pastuerella peritonitis, as well as an assortment of other bugs. Not to be outdone, rodents feature  in the case reports also, coining the term “hamster bite peritonitis” caused by pastuerella aerogenes.

In summary, technique and continuing re-education are of fundamental importance, as are topical antibiotics to prevent exit site infection.  Beyond this, trial data are severely lacking and local opinion and consensus must guide practice.

Authored by Eoin O'Sullivan

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.

Honey for the Achilles Heel

In the PD literature, peritonitis has been referred to as an Achilles’ heel because it could lead to catheter removal and PD treatment failure. Topical antibiotics have been used for prevention of an exit site infection (ESI) which may precede and lead to peritonitis.

For this purpose, most centers use mupirocin as their first choice. It has reduced the ESI significantly, but mupirocin-resistant S. aureus and P. aeruginosa ESI have emerged. Then came gentamicin which is superior to mupirocin. However, gentamicin-resistant P. aeruginosa has already been reported… How can we break this cycle?

FOOD was the bright idea! Not any food but a very specific sweet treat – honey. Honey has been applied to wounds since ancient times, but only recently have we come to understand its antibacterial properties: acidity (pH 3-4), high osmolarity (3000 mOsm/kg), H₂O₂, methyl glyoxal, bee defensin-1, etc. In vitro, honey killed bacteria including MRSA, β-lactamase producing E. Coli, ciprofloxacin-resistant P. aeruginosa and VRE! Because of its multiple antibacterial mechanisms, there is a low likelihood that bacteria will gain resistance.

But does it work in vivo? It has been shown that honey heals wounds and maintains sterility. Then, an Australian and New Zealand group tested standardized antibacterial honey (Medihoney) for HD catheter-associated infections and its effectiveness was comparable to mupirocin.

Now the same group is conducting the HONEYPOT study to see its efficacy in reducing the risk of PD infection. This is one of the initiatives to improve the PD technique survival in the region which is lower than in other parts of the world.

The results of the HONEYPOT study are pending, but it would be exciting if honey is proven to be an effective alternative prophylaxis with less chance of bacterial resistance. Penicillin was discovered from fungi. Gentamicin is synthesized by bacteria. Maybe it’s time to ask for honey bees for help.

Posted by Tomoki Tsukahara

Bactrim prophylaxis with high-dose steroid use?

This is a question we face quite often in the Nephrology clinic when we are commencing patients on high dose steroids for glomerular and other systemic inflammatory diseases.

I came across a couple of interesting retrospective studies while trying to find some evidence to help guide the decision-making process.

The first study analyzed 116 cases of pneumocystis pneumonia in non-HIV infected patients. The major common exposure was steroid treatment in the month preceding presentation (90.5% of patients) – the median dose was equivalent to 30mg prednisone for a median of 12 weeks before presentation.


The second reported risk factors in 41 cases in a French centre. Mortality was 29%; 85% had received steroids at a median daily steroid dose equivalent to 15mg prednisone. Only 17% had received prophylaxis.


The third used a matched case-control type analysis in patients with SLE – they reported 15 cases of pneumocystis infection; risk factors for infection compared to 60 matched controls included higher disease activity, renal involvement and higher mean cumulative steroid dose (49 vs 20mg/day; p<0.01).

Finally a Cochrane review of RCTs of prophylaxis against PCP (versus none/placebo/non-PCP agents) suggested that prophylaxis was warranted when the risk of PCP infection is higher than 3.5% for adults – the authors suggested this included the following groups – “recipients of solid organ or allogeneic bone allografts for the first 6 months after transplant and, for the latter, throughout the period of immunosuppression, as well as in patients with acute lymphoblastic leukemia and Wegener granulomatosis”


There are a number of factors to be considered when trying to answer this difficult scenario – the dose of steroids used, the duration of treatment, use of other immunosuppressive drugs (i.e. the net state of immunosuppression), medical co-morbid conditions and infection history.
Many experts suggest prophylaxis for patients with rheumatological diseases requiring treatment with ≥20mg prednisone for greater than one month when used in combination with another immunosuppressive drug. Overall the pros and cons of PCP prophylaxis must ultimately be judged on a case-by-case basis.

The dialysis patient with a hidden inflammatory state: a quick clinical assessment.

When caring for dialysis patients, we all use the well described KDOQI and KDIGO guidelines and ensure that the published goals are reached (please remember that the necessary government forms must also be completed!). We all pay special attention to the urea reduction ratio, the Kt/V, the PTH level and continuously test ourselves with the optimal management of “the uncontrolled hyperphosphatemic state". In addition to these markers and a physical examination (sometimes a forgotten cheap and valuable tool), I use a handful of specific laboratory tests which have helped me promptly determine the possible presence of a coexistent but hidden inflammatory state.

A reduced BUN/Creatinine ratio, an elevated total C02, a low uric acid level, a low Hb (specially if associated with a high ferritin level and a low reticulocyte count), a low cholesterol, a low phosphorus and a low albumin level are the ones which I have found to be most useful. In many outcome studies, several of these abnormalities have been found to be associated with increased mortality.

A low BUN/Creatinine ratio (i.e. characterized by a ratio ≤ 10-15/1) usually implies a low urea generation rate as a result of protein-calorie malnutrition, suboptimal dialysis and/or liver disease.
An elevated or inappropriately normal predialysis bicarbonate level as well as a low uric acid usually denotes the presence of decreased net acid generation as a result of malnutrition.
Low phosphorus, low cholesterol and/or low albumin levels are also seen as the result of malnutrition.
Resistance to the action of erythropoietic stimulating agents is usually suspected in the setting of an unresponsive anemia in conjunction with a hypo-proliferative bone marrow response (i.e. low reticulocyte index). This phenomenon can be the consequence of underdialysis, iron deficiency (as a result of decreased intake-administration, impaired utilization and/or increased losses) and endocrine dysfunction (e.g. hypothyroidism, uncontrolled secondary hyperparathyroidism).

In addition to the etiologies mentioned above, we should also consider (“think outside the box”) that any of them may also be caused by a common denominator – an inflammatory process. In addition to searching for an occult infection (particularly in patients with dialysis catheters), an ischemic skin ulceration, neoplasia, a clotting disorder, etc., we should also think of the retained clotted arteriovenous graft and/or the failed renal allograft as sources of malady! Clarification of their pathogenic role may not be easy as no clinical evidence of a problem (e.g. fever, renal allograft tenderness, hematuria, clotted AV graft warmth-erythema) may be noticeable (specially when patients returning to dialysis with a failed renal transplant are kept on “low dose prednisone”). Markers of inflammation such as an elevated ESR or CRP are useful but not specific. Nuclear studies using radiolabeled WBC’s and/or renal allograft biopsies are not only expensive-invasive but have not always being helpful. Therefore, we must always maintain a high index of suspicion and, if nothing else is found, we should remember that our friendly surgical colleague is just a phone call away!

Posted by Mario Rubin MD

Differential Diagnosis of Granulomatous Kidney Disease

Although it's not common (somewhere between 0.5 - 0.9% of all native kidney biopsies according to published case series), one of the fellows produced an interesting case of granulomatous interstitial nephritis in Renal Grand Rounds today.

The case, in a nutshell: a middle-aged individual with ESRD of unknown etiology who is now on a 2nd cadaveric kidney transplant which was transplanted about a decade ago, presented to the Transplant Clinic with a creatinine that bumped from its baseline of 1.8 mg/dL to 2.4 mg/dL and a urinalysis which was largely unremarkable with the exception of a few WBC casts. The patient was being treated with sirolimus 1mg po daily, MMF 500mg po bid, and prednisone 2.5mg po daily which had not been changed recently. A renal allograft ultrasound was unremarkable, as were tests for circulating donor-specific antibodies. The patient underwent an allograft biopsy, which surprisingly showed multiple granulomas in the renal parenchyma along with significant interstitital nephritis.

What's the underlying etiology of the granulomatous renal disease? To be fair, we don't yet know. Granulomas are essentially an organized collection of macrophages--they are often recognized by the presence of multinucleated giant cells, which are multiple macrophages which fuse together, and they can be broadly categorized as being either caseating (that is, containing a necrotizing core) or non-caseating granulomas. The following is a differential diagnosis of the most likely culprits:

1. Tuberculosis: TB is a classic cause of non-caseating granulomas. This patient worked in the health care industry and therefore had annual PPD tests, all of which were negative.

2. Fungal infection: Histoplasmosis and Cryptococcus are some of the more common granuloma-inducing fungal infections.

3. Other infections: Cat-scratch fever (caused by Bartonella henselae) and chronic pyelonephritis can sometimes cause granulomas to be seen on kidney biopsy, and in these instances the interstitial infiltrate is usually more neutrophil-rich.

4. Sarcoidosis: Although sarcoid most often manifests as pulmonary issues, it can really affect almost any site, including the kidney.

5. Wegener's granulomatosis: Evidence of pulmonary-renal syndrome and glomerulonephritis can raise suspicion for Wegener's. It's important to realize however that granulomas in the kidney are much more rare than granulomas in the upper respiratory tract.

6. Drugs: there are several reported instances of AIN producing granulomatous disease in the kidney. Somebody at RGR also suggested that perhaps sirolimus (known to result in other inflammatory complications such as pneumonitis and oral ulcers, for instance) should be considered as a culprit.

7. Idiopathic.

Due to the rarity of the condition, there is little consensus on how the condition should be managed. This case series by Joss et al in a 2007 issue of CJASN suggests that low- to moderate-dose steroids, after successfully ruling out infectious etiologies, can be beneficial.

Nephrotoxic HIV Drugs

I've done a post on renal-relevant HIV drugs previously, but I just heard an interesting case of tenofovir-induced renal failure at our Renal Grand Rounds and thought I'd mention a few interesting tidbits from the presentation.

1. HIV-Associated Nephropathy (a.k.a. "HIVAN"), which refers to the rapidly progressive GN characterized by a collapsing FSGS pathology on biopsy, is becoming less common with improved HAART therapy. Furthermore, HIVAN occurs almost exclusively in individuals with African ancestry, so it can usually be left off the differential diagnosis of non-African heritage patients with HIV and renal failure. Drug toxicities are accounting for a higher percentage of HIV-associated renal problems.

2. The mechanism of tenofovir toxicity is unclear but appears to have the most toxicity at the level of the proximal tubule, as affected individuals will usually exhibit a Fanconi's syndrome (with attendant phosphaturia, glucosuria, aminoaciduria, etc.) in addition to AKI. One thought is that tenofovir causes mitochondrial toxicity within proximal tubule cells specifically because the drug tends to concentrate there as tubular secretion is an important aspect of the drug's metabolism. Thus, patients with any degree of CKD should either avoid the drug altogether or get a dose adjustment; this can often be missed clinically as tenofovir is often given as a "combo pill" with other HAART medications (e.g., Truvada = tenofovir + emtricitabine; Atripla = tenofovir + emtricitabine + efavirenz).

3. The World Health Organization recently announced that tenofovir-based regimens be considered preferred, first-line treatment for HIV in developing countries. Apparently the authors of this report factored into account all the various HAART drug toxicities in their recommendations (the previously-recommended stavudine-based regimens also have significant toxicity in the form of lipodystrophy, lactic acidosis, and peripheral neuropathy), but the idea of using a drug known to cause AKI in countries where serum creatinine monitoring and dialysis is not routinely available could be troubling. This is obviously a complex topic, though, where a thorough risk/benefit analysis will be key.

4. Other drugs commonly used in the HIV population which may cause renal side effects include valacyclovir (associated with TMA), foscarnet (hypocalcemia, AKI), Bactrim (AIN, hyperkalemia), and crixivan (protease inhibitor which can cause nephrolithiasis).

Link Between CMV Status & EPO Requirements

Why do some dialysis patients require so much more Epogen than others? Some patients manage to hit their targets with relatively low doses, and may even require "holding" EPO injections to avoid the upper hemoglobin range where excess thromboembolic events occur; other patients struggle to achieve a Hgb greater than 10 despite massive doses of EPO and seemingly adequate iron stores. The variables are manifold, but one common assertion is that individuals with a high degree of chronic inflammation tend to be the ones with the greatest resistance to EPO.

A more novel link is reported in this month's JASN: a manuscript by Betjes et al describes an association between ESRD patients with CMV-positivity and those with EPO resistance. It turns out that individuals infected with CMV have an altered profile of T-cells: they tend to have high percentages of CD4+ T-cells which lack the co-stimulatory molecule CD28, whereas patients who are CMV negative contain very small (less than 5%) numbers of these cells. These CD4+ CD28- cells apparently are very pro-inflammatory, capable of secreting large amounts of IFN-gamma and TNF-alpha, which the authors cite as a plausible mechanism to explain why CMV-positive dialysis patients tended to have higher EPO requirements (12,000 units versus 6,300 units per week) than CMV-negative dialysis patients.

The study is potentially significant in that it implicates a common virus in aspects of the chronic inflammatory state known to be associated with poor outcomes in CKD and ESRD, and even points towards antiviral medications as a potential therapy for preventing some of the cardiovascular complications of ESRD. Of course, the big caveat is that the association does not necessary reflect causality; for instance, it may be possible that "sicker", more chronically-inflamed dialysis patients may simply be more susceptible to acquiring CMV seropositivity.

Leptospirosis-induced Renal Failure

T-Minus 2 days to the Nephrology Boards exams! For any of you out there studying, one useful resource is ASN's "NephSAP Core Knowledge Questions", which can be easily reached via the ASN web page. Unlike the main NephSAP questions which tend to ask for very specific details about the content of the NephSAP text (which often involves specific articles or newfangled molecular mechanisms which are unlikely to be tested in the Boards), the Core Knowledge Questions are more general and therefore more Boards-relevant.

Today's topic is leptospirosis, a zoonotic infection caused by the spirochete Leptospira interrogans. Leptospirosis is spread via exposure to contaminated tissue from a variety of mammalian hosts, often rodents (but can also include cattle, pigs, goats, horses, even dogs). While leptospirosis is most commonly found in tropical areas, it nonetheless has a worldwide distribution and can certainly be found within the United States, as evidenced by this outbreak of participants in an Illinois triathlon, who were presumably exposed while swimming in lakewater.

Up to 10% of individuals with leptospirosis will develop acute kidney injury. The mechanism of AKI is still under debate. Some have suggested that Leptospira endotoxin simply results in an inflammatory response, much like gram-negative LPS; usually, AKI occurs in the setting of multi-organ failure and critical illness. Others have suggested that Leptospira endotoxin has tubular toxicity, as evidenced by a high frequency of renal potassium-wasting and hypokalemia noted in these patients. Still others have stated that tubulointerstitial nephritis is the main mechanism of kidney injury in Leptospirosis. In some instances, rhabdomyolysis can be the main cause of Leptospirosis-associated AKI.

Treatment of Leptospirosis-associated AKI includes standard supportive measures, along with the use of antibiotics (either penicillins or tetracyclines are typically used).

Lyme Nephritis??

I included two question marks in the title, since the existence of Lyme Nephritis remains controversial.  However, somebody presented a case of alleged Lyme Nephritis in a recent Renal Grand Rounds which was interesting.

In brief, the case revolved around a resident of the Cape Cod area who presented with evidence of acute Lyme disease including several weeks malaise, nausea/vomiting and myalgias.  The patient was given a diagnosis of Lyme disease based on a positive IgM Lyme titer, and was treated with doxycycline.  At a return visit, it was noted that the individual had developed an acutely elevated creatinine (went from a baseline of 1.1 mg/dL to 1.8 mg/dL) and had a urinalysis showing hematuria, about 1 gram of proteinuria, and dysmorphic RBCs.  A renal biopsy was performed, demonstrating an immune-complex-mediated MPGN histologic pattern. Despite a thorough workup to exclude other causes of this type of injury (e.g., SLE, hepatitis, endocarditis, etc), nothing could be pinpointed, and based on the temporal association between the onset of Lyme infection and renal disease, a tentative diagnosis of "Lyme Nephritis" was considered the most likely.

There are other case reports in the literature of Lyme Nephritis (see 2004 AJKD article by Kirmizis et al), and furthermore it has been noted that dogs infected with Lyme disease frequently experience an often lethal glomerulonephritis.  However, Lyme Disease is common around these parts (somebody quoted a 1 in 5 Lyme infection rate amongst residents of nearby Martha's Vineyard, with rates of about 1 in 20 around the Cape Cod area), and it is possible that in this instance the Lyme Disease and GN are separate processes which just happened to occur at the same time.  

Renal TB

TB is classically thought of as a pulmonary disease--and in general, this is true, as pulmonary TB is by far the most common (and often very severe) manifestation of infection by Mycobacterium tuberculosis. However, the most common NON-pulmonary manifestation of TB worldwide is infection of the genitourinary tract, accounting for about 27% of non-pulmonary TB in most series according to this 2001 JASN review.

The name "renal tuberculosis" is a little misleading, since TB infection can actually cause renal problems by a variety of different mechanisms. Renal involvement may occur as part of a constellation of symptoms with miliary TB, in which there is mycobacterial "bacteremia/septicemia". The preferred site for mycobacteria in the kidney is the renal medulla, where caseating granuloma can lead to necrosis and tissue destruction, occasionally resulting in papillary necrosis. Large caseating necrotic areas can lead to a clinical picture very similar to pyelonephritis. Alternatively, infection in the lower urinary tract can lead to anatomic abnormalities, such as ureteric strictures, which over time can progress to frank obstruction and even ESRD. In addition to these more "mechanical" explanations for renal failure, there have been several reports that chronic tuberculosis infection is a potential cause for tubulointerstitial nephritis. In India, where TB is very common, AA amyloidosis secondary to the chronic inflammatory state induced by TB infection is a well-recognized cause of kidney damage.

Genitourinary TB may be diagnosed by culture or PCR of the organism from the urine (or sputum, if there is pulmonary involvement). Detecting acid-fast bacilli from the urine is another possibility though apparently this is less specific than culture or PCR as there are some environmental mycobacterial species which may colonize the lower urinary tract. Renal TB may be suspected if the patient has signs and symptoms of a urinary tract infection with a workup that demonstrates pyuria but a negative urine culture. Obviously, travel/occupational history plays an important role in identifying individuals who are at higher risk for TB. Another clue to the diagnosis of renal TB is hypercalcemia: instead of being mildly hypocalcemic like most advanced CKD patients, patients with TB infection may have high levels of 1,25(OH) vitamin D as a result of granulomas having the ability to synthesize active vitamin D, similar to the situation in sarcoidosis. In the U.S., a very low percentage of patients (.004%) list TB as a cause for their ESRD, but in some European countries (e.g. Greece) the percentage is as high as 5%, and likely much much higher than this in many African countries. It is important to recognize in that TB is very much a treatable disease (and therefore a preventable cause of CKD/ESRD).

3 Key Facts Regarding Catheter-Related Bacteremia

The following "3 Key Facts Regarding Catheter-Related Bacteremia" are taken from Eliot Heher's "MGH Nephrology Handbook" distributed to nephrology fellows every year which I find very helpful:

Fact #1:  Fever and chills are highly predictive of positive blood cultures in dialysis patients with tunneled cuffed catheters:  In this article by Krishnasami et al, 76% of the time blood cultures end up being positive in this instance.  

Implication:  All dialysis patients presenting with fever and a tunneled dialysis catheter should receive empiric antibiotic therapy while blood cultures are cooking in the lab.

Fact #2:  A significant minority of catheter-related bacteremia episodes result from GNRs (30-40%), with the majority arising from Staph species which are often methicillin-resistant.  Mixed bacterial and fungal infection are much less common.

Implication:  Empiric antibiotic therapy must include coverage for both GPCs and GNRs (e.g., vancomycin 1gm iv x 1 & gentamicin 1mg/kg iv x 1 given towards the end of dialysis).

Fact #3:  Systemic antibiotic therapy without additional catheter management fails to clear infection in about 70% of cases, according to this 1997 AIM article by Marr et al.  

Implication:  Some type of catheter management for catheter-related bacteremia should be attempted in addition to antibiotics.  Options include (a) removing the catheter (the safest option in terms of preventing bacteremic complications such as endocarditis), (b), changing the catheter over a guidewire, (c) or attempting catheter preservation using the "antibiotic lock" technique.   

The Legendary Walkerton, Ontario HUS Outbreak of 2000

In a recent Kidney International Supplement issue dealing entirely with TTP/HUS, there are two interesting articles regarding the Walkerton, Ontario HUS Outbreak: the largest public health disaster involving municipal water in Canadian history.

In May 2000, approximately 2300 residents (out of about 5000) of this rural farming town came down with a diarrheal illness caused by E. coli O157:H7. Essentially, a breakdown in public health checkpoints led to contamination of the water supply with the bacteria (shed by 20% of the cattle raised in the area) after a period of heavy flooding.

Not surprisingly, a significant number of cases of childhood HUS was reported: a total of 24 cases. One of the articles in this issue reports on the outcome of 22 of these 24 patients.

Patients with HUS were identified based on the development of anemia, hemolysis on blood smeark, a platelet count <> 95% for age and gender, and/or the appearance of hematuria or proteinuria. The mean age was about 5 but had a wide range. Eight of the children required dialysis, all of which was administered as peritoneal dialysis. There was one child who unfortunately died; of the survivors all fortunately were able to come off of dialysis eventually and a 1-year follow-up showed a GFR > 90cc/min per 1.73 m² in all but 2 patients.

The outbreak is interesting at a number of levels, including giving a large enough sample size to estimate the risk of developing HUS as a result of E.col O157:H7 exposure--only 24 of 564 children with diarrhea went on to develop HUS, leading to an estimate of about a 4% risk. This estimate is lower than previously suggested rates.

I wonder if there are any genetic differences to explain why certain children develop HUS in response to infection whereas others do not? This would certainly seem like a suitable and large enough sample size to begin asking these types of questions.

Basic Immunosuppression Prophylaxis Protocols

A quick & dirty guide for what kidney transplant patients should be on for prophylaxis:

1. PCP Prophylaxis: should be given to all patients for as long as they are on steroids. The standard is Bactrim SS given once per day (or given every other day for those with GFR less than 30 ml/min).

2. CMV Prophylaxis: I know that different transplant centers have different protocols for which antiviral agent is used for CMV prophylaxis, with choice of agent based on the CMV donor/recipient status. We tend to use valgancyclovir (Valcyte) most commonly given at 450mg po qd (or 450mg po qod if GFR less than 30.)

3. oral candidiasis: nystatin swish/spit is usually sufficient to prevent this.

4. Strongyloides: patients who are from an endemic area can be given ivermectin 200mcg/kg po x 2 doses which is highly effective.

Antibiotic Lock Solutions for Catheter-Related Bacteremia

It doesn't take long for the renal fellow to realize that a huge chunk of ESRD hospital admissions are due to catheter-related bacteremia, and a number of different algorithms exist for the management of dialysis catheter-related infections. Typically, this involves removal or exchange of the catheter in association with iv antibiotics targeting gram-positive (and sometimes gram-negative) organisms. More recently, another strategy has been suggested for the management of catheter-related bacteremia: antibiotic lock solutions. What is their current role?

The antibiotic lock method--which remains controversial and is specifically not recommended in the "Up To Date" section on "Management of infected cuffed central venous catheters used for hemodialysis"--involves the installation of an antibiotic solution into the hub of the catheter and allowing it to dwell for a particular length of time. This could conceivably be used either for treatment of existing bacteremia or for the prevention of bacteremia as a prophylactic.

Most of the existing evidence look at the use of antibiotic lock solution as a preventative measure. A 2008 meta-analysis of 7 studies (which combined measured >800 catheters) looking at a variety of different antibiotic lock solutions demonstrated a greater than 7-fold less likely risk of developing catheter-related bacteremia, suggesting that the practice is sound. However, there are still concerns regarding (a) the emergence of antibiotic resistance as a result of broad acceptance of this practice, (b) whether or not the prolonged use of antibiotics could conceivably result in toxicities to the patient due to some degree of systemic absorption, and (c) exactly how such a treatment would be paid for.

There is much less data on the use of antibiotic lock solution as treatment of existing bacteremia, and much of it is on non-dialysis catheters. I can't think of anybody that would recommend using antibiotic lock solution by itself as a treatment regimen for catheter-related bacteremia; it would have to be in addition to systemic antibiotics. A good review of the literature can be found here.

Schistosomiasis and Renal Disease

Schistosoma species--also known as blood flukes and bilharzia--can cause some interesting forms of renal disease. Although this is not so common in the United States, it is a very common public health problem in Africa and Asia.

Chronic Schistosoma mansoni infection in about 10-15% cases is associated with a glomerulonephritis. The etiology is not entirely clear but there is evidence that both schistosomal antigens and antibodies against them can be found in glomeruli from biopsy specimens. Similar to the WHO Classification System for lupus, there is a classification system for schistosomal glomerulopathy which has been set forth by the African Association of Nephrology (AFRAN), and there is an interestingly wide variety of pathologies which can result:

-Class I is a mesangial proliferative GN, the recovery from which is generally good.

-Class II is an exudative GN which is classically observed in patients who are co-infected with both Schistostoma as well as Salmonella (apparently common in some regions).

-Class III is an MPGN.

-Class IV is a proliferative sclerosing GN. Classes III & IV are the most common and most severe form of the disease, which may present as an FSGS-like nephrotic syndrome. Concomitant liver disease (common with Schistosomiasis) and IgA deposition are also suggested to play important pathogenic roles.

-Class V is an AA amyloidosis secondary to chronic inflammation from Schistosomiasis.

Schistosoma hematobium, in contrast, is associated with bladder cancer, particularly in the Middle East. Individuals with Schistosomal-induced bladder cancer are generally treated with radical cystectomy with lymph node dissection, with possible roles for adjuvant or neoadjuvant chemotherapy which are still being determined.

Treatment of Sepsis

I heard a talk on "Sepsis & Renal Failure" today, which reviewed much of the recent evidence-based medicine trials regarding the treatment of sepsis in the ICU.

Honestly, the main message I came away with was this: most of the purported "advances" in sepsis treatment I learned in residency are probably not that useful. Let me explain: As an internal medicine resident, there were a four hot ICU papers that were repeatedly emphasized. They were:

#1: "early goal-directed therapy" by Rivers et. al. published in NEJM 2001. This protocol-driven ER-based study showed that keeping the MAP >65 with fluids and inotropes, the CVP between 8-12, and transfusing blood to achieve an SvO2 >70% & Hct >30% was associated with improved mortality in sepsis patients. This is one of the few studies which hasn't been debunked, so it is still in use.

#2: steroid therapy. I was taught to perform a cosyntropin stim test to determine if sepsis patients were "relatively adrenally-insufficient", and if so to give a give low-dose steroids with hydrocortisone 50mg iv q6h and fludrocortisone as well. Most of the time we gave the steroids right off the bat and took them off only if the cosyntropin test came back negative the next day or so. However, a more recent NEJM 2008 study (the CORTICUS trial) shows a pretty convincingly negative result for this practice.

#3: Intensive insulin therapy. It was also en vogue to be pretty aggressive with insulin drips in the ICU in an attempt to achieve tight glucose control in the setting of sepsis, reasoning that hyperglycemia can have a cell-toxic effect. The recent VISEP study was a large trial which (among other things) compared an intensive glucose control strategy to a more conventional one: the intensive glucose control strategy showed no mortality benefit, while showing many more hypoglycemic episodes.

#4: Activated Protein C (Xigris). The possibility that derangement of the coagulation cascade plays a role in sepsis led to the development of activated protein C (drotrecogin alfa, or Xigris) for use in sepsis patients. An NEJM study showed a mild beneficial effect (31% versus 25% mortality) in the PROWESS trial, a randomized control trial. Even though the effect was small and the drug was expensive, as residents we were encouraged to give the drug under the rationale that these patients were super-sick and they needed any advantage they could get in order to make it through. However, a more recent trial, ADDRESS, looked at septic patients who were slightly less sick (e.g., lower APACHE thresholds for administering Xigris) and found no mortality benefit and an increased rate of hemorrhage in the Xigris group compared to placebo.

So of these four "breakthroughs" in the treatment of ICU sepsis, the efficacy of three have been seriously called into question through the use of large, seemingly well-designed randomized control trials. It appears that more creative approaches will still be needed to come up with better therapies for this high-mortality (and highly renal-toxic) condition.