Tuesday, June 29, 2010

Achilles heel of dialysis

Vascular access is the Achilles tendon of hemodialysis. Just yesterday, I saw a patient with one of those lumbar catheters… Examining his arm revealed that he had failed 4 attempts of access creation (2 fistulas and 2 grafts). With that in mind, let’s start by reviewing the key components for a successful AVF creation: in our hospital, evaluation before placement of a fistula starts with:

*Dopplers of the upper extremities.
*The arterial lumen should have > 2.0mm at the point of anastomosis and the venous side should be at least 2.5mm.
*Ensuring that there are no proximal venous stenosis is also key, since some patients had lines before that increases the risk of subclavian stenosis, leading to inadequate maturation of the access.

Many of the diabetic patients have very small vessels, creating a special challenge for fistula maturation.


The order of preference for AVF creation once vessel size is confirmed is the following:
  1. radial-cephalic
  2. brachial-cephalic
  3. brachial-basilic transposition.
Once the AVF is created, the rule of 6 apply in order to decide about usage (as discussed by Nate).

6 weeks after the AV fistula has been placed, the fistula should:
(a) be able to support a blood flow of 600 ml/min.
(b) be at a maximum of 6mm from the surface.
(c) have a diameter greater than 6mm.

There are multiple reasons for a fistula not to mature, but the main causes of early fistula failure can be classified as:

Inflow problems: pre-existing arterial anomalies (anatominally small, atherosclerotic disease) or acquired (juxta-anastomototic stenosis)

Outflow problems: pre-existing venous anomalies like anatomically small, fibrotic vein, proximal venous stenosis and accessory veins.

As you can see, an adequate evaluation with dopplers can usually ensure no pre-existing vascular conditions exist, leaving the 2 most common causes of early AVF failure as the presence of accessory branches and juxta-anastomotic stenosis. Early recognition is essential, since vascular interventions can save the fistula on both the above occasions.

Typical HUS: beyond shiga

Hemolytic Uremic Syndrome is characterized by the triad of
  1. Microangiopathic hemolytic anemia
  2. Thrombocytopenia
  3. Renal failure.
The disease is broken down into
  • Typical, or diarrhea associated
  • Atypical, or diarrhea negative cases.

90% of HUS cases in the United States are diarrhea associated and Shiga toxin producing E coli O157:H7 is identified in the majority of these.

Recently, a novel Shiga independent mechanism has been proposed for typical HUS involving the virulence factor subtilase cytotoxin (SubAB), which is sometimes present in E coli O157:H7 and other strains of Shiga toxigenic E coli.

SubAB binds to the sialic acid, Neu5Gc which humans are unable to synthesize leading to proteolytic cleavage of an endoplasmic reticulum chaperone triggering a endoplasmic reticulum stress response and eventual cell death.

So where does Neu5Gc in humans comes from? It appears to come from the diet, primarily from red meats and dairy products, the very food types that are sometimes contaminated with Shiga toxigenic E coli.

Once ingested, Neu5Gc is incorporated onto the surface of endothelial, and to a lesser extent intestinal epithelial cells.


In this “two-hit” model those who regularly consume red meat and dairy are potentially priming their intestinal and endothelial surfaces with Neu5Gc while also increasing the likelihood of eating a meal containing a SubAB producing bacteria. This model is nicely summarized in a KI review by Lofling and colleagues.

In a previous post dealing with the Walkerton Ontario HUS outbreak Nate wondered what factors contributed to development of disease in patients with E coli O157:H7 associated diarrhea.

Perhaps, SubAB and previous dietary priming with Neu5Gc are parts of the puzzle.

Graham Abra, MD

Monday, June 28, 2010

Vas-cath exposure variability













How many vas-caths did you (the renal fellow) place during your clinical year (1 year)?
Poll results:
A. 0-5 (IR does most of these) 4 (4%)
B. 0-5 (Surgery does most of these) 2 (2%)
C. 0-5 (IM residents do most of these) 3 (3%)
D. 0-5 (combination of IR, Surgery and IM) 12 (13%)
E. 6-10 8 (9%)
F. 11-25 17 (19%)
G. 26-50 16 (18%)
H. 51-100 12 (13%)
I. 101-150 11 (12%)
J. 151-200 2 (2%)
K. >201 4 (4%)

Total Respondents- 91

Looks like there is quite a bit of variability in the number of vas-caths performed by renal fellows. I was actually a little surprised by this. Looks like the majority of folks perform anywhere between 11-100 vas-caths in a year. However, 22 (24%) fellows actually placed fewer than 5 (majority were placed by a combination of VIR, Surgery & IM residents) in a year. 4 fellows placed >201 in a year, quite an impressive number for sure. I'm fairly confident that the number of vas-caths placed by fellows is decreasing somewhat each year. I bet this is from the rise of vascular interventional radiology gobbling up all of the procedure in the hospital. I wonder what this data would look in 4-5 years from now.

Thursday, June 24, 2010

Therapeutic misadventures in rhabdo

There are three commonly promoted strategies used in the treatment and prevention of AKI in rhabdomyolysis: 1) Normal saline 2) Bicarbonate containing solutions 3) Mannitol.

Volume resuscitation is clearly paramount when treating rhabdo, but whether bicarbonate or mannitol is beneficial is controversial. The figure below from a recent NEJM review gives a nice overview of the state of the literature.


Regardless of what therapy is ultimately decided upon it’s important to keep in mind that each can lead to unique but potentially counterproductive complications.

Hypocalcemia – Bicarbonate containing solutions have some attractive features based on animal data suggesting that they reduce:
1) Tubular precipitation of Tamm–Horsfall protein–myoglobin complexes
2) Generation of injurious oxidation products
3) Afferent arteriole vasoconstriction induced by metmyoglobin.


Unfortunately, in addition to these theoretical benefits, alkalinization of the blood pH can lead to increased calcium complexing with albumin thus decreasing physiologically active ionized calcium. This complication can be particularly problematic (eg tetany) early in rhabdo when serum calcium is dropping due to movement into damaged muscle and precipitation from serum as calcium phosphate.

Non-Gap Acidosis – Normal saline is used as an intravascular volume expander to replace fluid as it moves into damaged muscle.

Large volumes of NS are sometimes required in rhabdo and can lead to “dilutional acidosis.” There are several proposed mechanisms behind this that are nicely discussed in one of Nate’s prior posts. If clinically significant, lowering of the serum pH and subsequently urine pH could potentiate all of the mechanisms bicarbonate therapy experimentally mitigates.

Osmotic Nephrosis – The use of diuretics is again, controversial (must mean something when that word keeps popping up!) but in volume replete patients mannitol has several sited benefits.

Its main effect is as an osmotic diuretic leading to increased urinary flow and the flushing of nephrotoxic agents through the tubules. It also acts as a free-radical scavenger and an intravascular osmotic agent reclaiming fluid from injured muscles. Unfortunately, when large quantities of mannitol (greater than 200g/day or accumulated doses of greater than 800g) are used they can lead to renal vasoconstriction and direct tubular toxicity. This brand of AKI is termed osmotic nephrosis and histologically appears as tubular cytoplasmic vacuolization.

Pseudohyponatremia – Mannitol has the additional potential complication of hypertonic hyponatremia.

As an effective serum osmole, mannitol raises serum osmolality and pulls free water into the intravascular space diluting the serum sodium concentration. The effect on serum osms can lead to significant serum hypertonicity resulting in seizures as the brain shrinks.

Graham Abra, MD

Wednesday, June 23, 2010

World Cup fever

Congratulations to the USA and England on going through to the second round of the World Cup today. As an Irishman, I will confess to a modicum of schadenfreude at the humiliating exit of France yesterday, but we won't dwell on that... Unlike high-contact sports such as Rugby or American football, it seems possible to play soccer to a high level after a renal transplant. Ivan Klasnic, a Croatian who plays for Bolton in the English Premiership and the Croatian National team, is one such example. He developed ESRD in January 2007 and received his first transplant from his mother later that month, but unfortunately this was lost to rejection 5 days post-transplant. However, a second transplant from his father 7 weeks later was successful. He was back playing for FC Nantes one year after first becoming ill, wearing a protective belt over the transplant site. He went on to play a starring role in the Croatian National team in Euro 2008, the first transplant patient ever to do so, scoring in both the group stages against Poland and the quarter-finals against Turkey.
It hasn't all been plain-sailing though - England's controversy-prone John Terry allegedly punched him in the transplant during a match last year... a crime only marginally worse than a deliberate handball in the closing minutes of a crucial world cup qualifier, but maybe I'm biased...

Tuesday, June 22, 2010

Of snakes and men

As mentioned in a previous post, there is not much salt available in the Amazon and as a result, the inhabitants (human and otherwise) have developed very active renin/angiotensin systems in order to retain whatever salt they can find. Nature being what it is, some predators have evolved to take advantage of this.

Bothrops Jaracara, or the Brazilian Pit Viper, is a poisonous snake that lives in this region. Along with anticoagulants, in the 1960s it was discovered that its venom contains "bradykinin potentiating peptides" that inhibit the angiotensin converting enzyme. In this salt-deprived environment, a bite from this snake would rapidly lead to hypotension and syncope. Captopril, the first commercially available ACE inhibitor, was derived from these peptides in the 1970s. Thus, something which provided a competitive advantage to a viper in the Amazon has become a mainstay in the treatment of hypertension and renal disease today. Similar peptides have been found in the venom of another snake, Agkistrodon Halys Blomhoffii, which is native to Japan and China.

Thank you to commenter Trevedy who pointed me in the direction of an article on the origin of ACE inhibitors.

Monday, June 21, 2010

The bad habit of ACEI!!!!

Coming to the transplant clinic from 2 years of CKD clinic, prescribing ACEI/ARBs was a habit, a good one I guess. Does this hold truth in the transplant world, well... I am not sure anymore after I read this meta analysis in Transplantation last year. The reason simply is that kidney recipients are biologically different from CKD patients. Most of our kidney transplant patients are on calcineurin inhibitors (CNI) which induce afferent arteriolar vasoconstriction. Thus, the advantage of calcium channel blockers (CCB) over ACEI in this population is that it may promote vasodilation of afferent arterioles which may counteract CNI’s effect.
In this meta analysis of 60 trials, enrolling 3802 recipients:
· 29 trials (2262 patients) compared calcium channel blockers (CCB) with placebo or no treatment
· 10 trials (445 patients) compared angiotensin-converting enzyme inhibitors (ACEi) with placebo or no treatment
· 7 studies (405 patients) compared CCB with ACEi
CCB compared with placebo or no treatment (plus additional agents in either arm as required) reduced graft loss (risk ratio [RR] 0.75, 95% confidence intervals [CI] 0.57–0.99) and improved glomerular filtration rate (GFR; mean difference [MD] 4.5 mL/min, 95% CI 2.2–6.7).
Data on ACEi versus placebo or no treatment were inconclusive for GFR (MD -8.1 mL/min, 95% CI -18.6–2.4) and inconsistent for graft loss, precluding meta-analysis.
In direct comparison with CCB, ACEi decreased GFR (MD 11.5 mL/min, 95% CI 7.2–15.8), proteinuria (MD 0.28 g/day, 95% CI 0.10–0.47), hemoglobin (MD 11.5 g/L, 95% CI 7.2–15.8), and increased hyperkalemia (RR 3.7, 95% CI 1.9–7.7). Graft loss data were inconclusive (RR 7.4, 95% CI 0.4–140).

So according to this study there is no advantage of ACEI/ARBs over CCB, with more side effects from angiotensin inhibitors. Obviously, a good randomized trial is needed to resolve this issue.
These data suggest that CCB may be preferred as first-line agents for hypertensive kidney transplant recipients and the KDIGO guidelines consider ACEI/ARB as first line therapy for HTN in renal transplant patients only if their proteinuria is > 1gm/day. A good practice would be to hold them in acute illness as those patients are very sensitive to dehydration due to afferent arterioles vasoconstriction by CNI.

Board question: Transplant-1 answer



The vast majority of people answered correctly; the best answer is D.


Approximately 3-5% of patients with Alport's syndrome develop de novo anti-glomerular basement membrane (GBM) disease in the transplanted kidney. Alport’s syndrome is a genetic disorder that results from mutations in the genes encoding the alpha-3, alpha-4, or alpha-5 chains of type IV collagen. Following transplantation, recipients can become alloimmunized and develop antibodies to the normal chains of type IV collagen in the basement membrane of the donor kidney (hence, the linear pattern of staining noted on IF). Treatment is not standardized, but generally consists of plasmapharesis, +/- cyclophosphamide and steroids. Long-term allograft survival is poor and re-transplantation carries a high risk of anti-GBM recurrence. For the boards, remember the post-transplant association between Alport’s syndrome and de novo anti-GBM disease.

Link to NEJM review which contains above picture


Michael Lattanzio DO

Saturday, June 19, 2010

No salt, no hypertension

Back in the early 1970s researchers traveled into the jungle in Northern Brazil to visit a group of Indians. The Yanamomo tribe had lived in isolation for thousands of years and had only been contacted in the 1950s. What made them a subject of interest was their diet; their staple food was a kind of large cooking banana, supplemented occasionally with game, fish, wild vegetables and insects. This diet contained almost no salt. At the time, it was regarded as normal that blood pressure rose gradually with age. However, the BP of the Yanamomo Indians remained remarkably stable throughout life, ranging from 107/66 in teenagers to 100/63 in those >50. The investigators went on to perform 24h urine collections on a number of the Indians – this was difficult – in their own words “the collections were complicated by the rather difficult conditions under which the work was conducted as well as the free and unfettered nature of the Yanomamo psyche, which found it difficult to take seriously the concept of a 24 hr urine”. Despite this they managed to acquire complete collections on 26 male subjects and took a series of collections on themselves as western controls.


The results were remarkable.


  • The mean 24 hr sodium excretion was 1mEq/24hrs in the Indians compared to 152 mEq/24hrs in the controls.
  • Potassium excretion was 152 v 38 mEq/24hrs and Chloride was 14 v 102 mEq/24hrs.
  • Urinary aldosterone excretion was 75 v 3 ug/24 hrs.
  • The plasma renin activity was also significantly higher in the Indians.
The high potassium/low sodium diet that they were consuming resulted in appropriate hyperaldosteronism in the absence of hypertension. It is likely that this diet is similar to the one our ancestors in Africa were accustomed to. Perhaps the low level of aldosterone that we regard as normal in the west is actually an adaptation to the extremely high level of salt in the western diet – certainly, these Indians prove that we can survive comfortably on less than 1% of our usual salt consumption. It is interesting to note the extremely high urinary anion gap in the Indians – mean 130. What was the anion excreted with the potassium? In all likelihood this was bicarbonate. The potassium in bananas exists in the form of potassium citrate and this would need to be excreted along with the potassium to maintain normal acid-base balance. Unfortunately we do not have any record of the acid base status of the subjects so that is a subject for conjecture. Other studies of isolated tribes who were contacted in the last 70 years have shown a gradual rise in BP in the years after contact. This may be due to increasing quantities of salt in their diets as they are “civilized”.

Here is a previous post from Matt on dietary salt reduction.

Friday, June 18, 2010

Ultrasound guided vas-cath placement

Much of the clinical year of the renal fellow is spent in the hospital rounding on patients admitted with access malfunction, catheter related infections or are in the ICU's with acute kidney injury. Many of these patients will require temporary dialysis access that in many cases will be life saving. Nate has already nicely discussed the debate between when to choose the femoral vs. the internal jugular vein in a previous post. These lines have the potential to pose many difficulties as patients with renal failure can have difficult and limited access sites. A difficult line can be avoided with appropriate training and imaging. We are fortunate to have an ultrasound readily available in our dialysis unit for vas-cath placement, but many hospitals do not.

An interesting article was published in the Feb 2010 CJASN by Prabhu et al in which 110 patients were randomized into two groups. One group had ultrasound guided femoral catheter placement and one group did not. The results, not surprisingly, showed that patients who had ultrasound guided vas-cath placement had a higher overall success rate (98.2% vs. 80%), better first attempt success rate (85.5% vs. 54.5%) and had few complications (5.5% vs. 18.2%). Furthermore, of the 11 patient who did not have a successful catheter placed without ultrasound guidance, 10 of these had success with use of the ultrasound in the exact same leg. This article also reviewed 3 other studies comparing ultrasound vs. standard landmark techniques. These studies show similar results.

Another interesting article was published in AJKD in 2009 by Barsuk et al from Nothwestern University. This study looked at the use of an ultrasound compatible central line simulator (like on the picture above) and deliberate practice before actually placing lines on patients. Again two groups were assessed in an unblinded fashion.


  • Simulator Group- 12 first-year fellows were trained with the simulator and tested before and 2 weeks after the intervention with a 27 item clinical skills examinations checklist (available from the supplementary data).
  • Traditional Group- 6 graduating second-year fellows were tested using the simulator once during the last 2 months of their fellowship.

Results from this study also showed benefit using the central line simulator. Interestingly, only one of the six graduating fellows met the minimum passing score. The simulator group improved dramatically from a score of 29.5% to a score of 88.6%. The course was highly rated by the attendees. It would be interesting to see if complications rates went down after the intervention. Also, I wonder if the higher scores would hold up over time. If I took the same test in a 2 week interval, I'm pretty sure I would score much higher on the second attempt. Especially after attending a 2 hour course.

I hope that more nephrology programs begin instituting programs like the simulator course. Likewise, ultrasound guided vas-cath placement needs to become standard practice. This can only help patient care and improve the competency of the graduating fellows. That being said, how many times do nephrologists in private practice put in temporary catheters? As the interventional radiology field continues to grow, this is surely decreasing.

Thursday, June 17, 2010

Board question of the week: Transplant-1

An 18-year-old white man presents to the renal transplant clinic with complaints of fatigue and nausea for the last week. He was the recipient of a deceased donor kidney transplant 12 months prior and has experienced stable allograft function (Cr 1.2 mg/dL) thereafter. His original renal disease was Alport’s syndrome. His current immunosuppressive regimen consists of tacrolimus and mycophenolate mofetil. He reports strict compliance with this regimen. The nephrologist orders bloodwork:

Bun-50 Cr-5.0 UA-3+ blood 3+ protein dysmorphic RBCs noted
Spot protein/creatinine ratio- 5g/d
C3/C4- normal, FK506 level- 10

Renal transplant ultrasound- no gross abnormality

ANCA pending

Given the worsening renal function, a transplant biopsy is immediately performed. The light microscopy and immunofluorescence appear below:












The answer and explanation will be posted on Monday June 21st

Michael Lattanzio DO


*RFN board questions are meant to help introduce concepts about nephrology related diseases and do not represent actual questions seen on the ABIM exam.

Evaluating incidental renal cysts

Last week, I got an email from a residency friend asking me what I would do with a patient who had a Bosniak II renal cyst. Since “I don’t know” no longer seemed a satisfactory answer for someone who specializes in kidneys, I looked it up, returned her email, then decided to review the radiologic classification of renal cysts on the blog, for anyone else who would like a refresher. An excellent review by Glickman et al can be found in the journal Radiology.

Renal cysts are masses filled with fluid. They are extremely common: some studies have estimated their incidence in the general public at around 50%. Most are discovered incidentally, since they rarely cause symptoms. Flank pain and hematuria are occasionally seen. Radiologic features of renal cysts convey important information about their malignant potential—our main concern as physicians. Does the wall of the cyst appear thin and simple, or does it have a thickened lining? Is the fluid in the cyst attenuated? How heterogeneous does the cyst appear? Are there septae or enhancing soft tissue components? In 1986, a classification scheme was published by Bosniak that stratified malignant risk based on characteristics of the cyst on CT scan. The Bosniak classification remains a useful guide for management of incidentally-discovered renal cysts. It should be emphasized, however, that evaluation of cysts must take into account a patient’s demographics and medical history: a diagnosis cannot be made by imaging alone.

Bosniak Classification of Renal Cysts

Bosniak I- benign, simple cysts, with thin walls. Note that size is not a factor in classifying cysts in this category. Bosniak I cysts are always benign, and can be ignored. These cysts are not attenuated, and tend to have Hounsfield units of 0-20.

Bosniak II- benign, minimally complicated cysts; may have hairline-thin septa with some perceived enhancement. There may be fine calcification or areas of calcified thickening along the wall or septa. Fine calcification or a short segment of slightly thickened calcification may be present in the wall or septa. Homogeneous hyperattenuating cysts also belong in this category—high Hounsfield units usually signify proteinaceous fluid. Bosniak II cysts are also felt to have non-malignant potential, and can be ignored by the physician.

Bosniak IIF- these are slightly more complicated that class II cysts, and so warrant observation. IIF cyts may contain multiple, hairline-thin septa that demonstrate perceived (but not measurable) enhancement. There may be minimal smooth thickening of the wall or septa. Calcification that is more irregular and thicker than in Bosniak II cysts may be present. Soft tissue elements are absent. Hyperattenuating cysts otherwise classified as category II cysts, but are > 3cm and completely within the renal parenchyma are included in class IIF. The general recommendation for observation of these cysts is to reimage with CT or MR in six months, then yearly for a minimum of five years. If they remain stable, it can be assumed that they are benign, and no further follow-up is needed.

Bosniak III- the malignant potential of class III masses is indeterminate on imaging; therefore, surgical removal is recommended. These cysts have thickened walls or septa, and display enhancement. They include multilocular cysts (in which the walls have fibrous lining), hemorrhagic or infected cysts, multilocular cystic nephroma (which conatin blastemal elements), or cystic renal cell carcinoma. It is estimated that 50% are malignant (studies have shown malignancy rates ranging from 31% to 100%).

Bosniak IV- share features of Bosniak III, plus enhancing soft-tissue components adjacent to or separate from the wall or septa. They are almost always malignant. Management is surgical.


The Bottom Line: radiologic followup is needed only for class IIF lesions. The others are either ignored or referred for surgical management secondary to the high rates of malignancy.

Tuesday, June 15, 2010

Hypokalemia and deafness

I attended a research seminar last week given by the discoverer of EAST syndrome. This a rare, autosomal recessive condition in which children present with Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy. It was a fascinating lecture detailing the slow but painstaking process whereby they first realized that this was a unique condition and slowly, over time, discovered the cause. It is due to a defect in KCNJ10, a potassium channel expressed on the TAL, distal tubule and early collecting duct. It is thought that it allows potassium to escape the cell and hence is required for the proper function of the Na/K-ATPase. Affected patients present with hypokalemic metabolic alkalosis and salt-wasting. It is also expressed in the inner ear and the brain, particularly in the cerebellum, thus explaining the ataxia.

This made be wonder; how many other conditions exist where hypokalemia is associated with sensorineural deafness?

Antenatal Bartter syndrome with sensorineural deafness: This disease is due to a mutation in the gene BSND, which encodes for Barttin. Barttin is the beta subunit of the chloride channels ClCKA and ClCKB, expressed in the distal nephron and the inner ear. Affected children present with polyhydramnios, premature birth and severe neonatal salt-wasting. The deafness is progressive and irreversible. Unlike other forms of antenatal Bartter syndrome, it is not associated with nephrocalcinosis and does not respond to indomethacin. Although it often progresses to renal failure, this is not inevitable and milder phenotypes have been described.

Distal Renal Tubular Acidosis and Sensorineural Deafness: First described in 1966, this is an autosomal recessive disease caused by a mutation in the gene ATP6B1 leading to a defect in the H-ATPase. It is primarily expressed in the distal nephron but is also required for the maintenance of proper endolymph pH in the inner ear. Patients present with type 1 RTA, nephrocalcinosis, poor growth and irreversible sensorineural deafness.

Pendred Syndrome: This disease is thought to cause 10% of congenital deafness and was detailed in a previous post by Nate. It is due to a defect in HCO3-Cl exchange in the collecting duct. Affected patients are not usually hypokalemic under normal circumstances. However, they develop a hypokalemic metabolic alkalosis on treatment with thiazide diuretics, which is reversible on stopping the drug.

Mitochondrial Cytopathies: Sensorineural Deafness is a common problem in patients with mitochondrial disease and about 5% of patients have renal involvement; most commonly represented by the fanconi syndrome with RTA, hypokalemia, glucosuria and aminoaciduria presenting prior to 2 years of age. They can also be associated with glomerular disease and could be confused initially with Alport’s syndrome although hematuria is usually absent in these patients.

Honorable mention must go to loop diuretics, which along with causing hypokalemia, can lead to ototoxicity, particularly when used in high doses. They cause edema of the epithelium of the stria vascularis by changing ionic gradients between the perilymph and endolymph and the resulting hearing loss can be permanent.

Finally, there is a single case report from Japan of a patient who developed permanent unilateral sensorineural deafness following an episode of hypokalemic periodic paralysis. His potassium on presentation was 1.5 mmol/L and the deafness was thought to be due to an electrolyte imbalance in his inner ear.

Sunday, June 13, 2010

National Course for Renal Fellows; Origins of Renal Physiology

Listen to a podcast from Dr. Mark Zeidel about the Origins of Renal Physiology course at Mount Desert Island held every September in Maine. This course is a great opportunity to learn about renal physiology "hand's on" with world renowned researchers and an even greater opportunity to get to know other fellows from around the country and world. I attended this week long course two years ago with Nate. Many of the attendee's still communicate regularly. The course directors did a great job teaching and keeping the material interesting. Each fellow will get experience in three separate modules focusing on a different segment of the nephron. After a day of experiments and data analysis, the next morning is spent giving presentations about the results obtained. The rest of the day is free to explore the Island. Overall, I thought the course is a unique experience and shouldn't be missed. The course fee continues to drop each year (currently $900- which including food and lodging) and hopefully, as Dr. Zeidel explains in the podcast, the fee might be reduced to free in years to come.

Thursday, June 10, 2010

Falls and dialysis

The recent death of the actor Gary Coleman after a fall in his home brought to mind the issue of falls in dialysis patients. Gary was best known for playing the role of Arnold in the TV show Different Strokes. He had congenital nephrotic syndrome and had two renal transplants, in 1973 and 1984. Over the last few years he had been on regular hemodialysis. He had dialysis on the morning of his fall and one of his friends reported that he had been feeling very weak after the session. Unfortunately, he fell at home that afternoon and suffered a head injury from which he did not recover.

There are only a few papers that directly address the issue of falls in dialysis patients. One study prospectively followed 308 dialysis patients of all ages for 8 weeks and found that 13% of patients fell at least once with 80% of the falls occurring at home. In the 12 months after the close observation period ended, 4% of patients suffered a fall-related fracture. Falls were independently associated with polypharmacy, increasing age, diabetes, use of anti-depressants and, unsurprisingly, failing functional tests at the beginning of the study period.

Another study divided 78 dialysis patients into younger (less than 65yrs) and older age groups and followed them for 6 months. Rates of dizziness (80%), pre-syncope (50%) and syncope (20-30%) were similar in the two groups but falls were much commoner in the older cohort (38% v 4%). The rate of falls in the older patients was 1.76/patient/year, which is higher than the rate recorded for elderly nursing home residents.

These falls are not without serious consequences, the rate of hip fractures is 3-4 times higher in dialysis patients than in the general population. Some of this risk is related to reduced bone mineral density but some is related to the increased risk of falls. The one-year mortality for hip fracture in dialysis patients is 40-60%.

So what can we do to prevent falls in our patients? The first thing is to identify patients at risk, particularly those who have a history of previous falls. Avoid overly aggressive fluid removal and reduce the number of medications the patients are taking if possible. Randomized trails have demonstrated the effectiveness of a multidisciplinary approach to falls in non-dialysis patients. This includes review of medications, strength and gait testing with targeted training, assessment of the home environment and measuring visual acuity. These strategies are likely to be effective in dialysis patients also and could help reduce the morbidity associated with falls in this vulnerable population.

Wednesday, June 9, 2010

Graduating renal fellow survey

Time is running out for graduating fellows to complete the quick 9 question survey to find out what kind of jobs are out there. It only takes a minute! RFN will take the poll down in a week then Dr. Deepti Torri and Dr. Kellie Calderon will compile the results and report back to RFN with the results. Click here to take survey

A Grey Area: warfarin for atrial fibrillation in dialysis patients

I recently wrote a short post detailing safety concerns surrounding warfarin use for atrial fibrillation (AF) in dialysis patients. I focussed mostly on the emerging evidence that it may promote vascular and valvular calcification by the inhibition of vitamin-K dependent gamma-carboxylation, as well as recent observational data linking warfarin use to higher mortality rates in ESRD. I finished the piece with this line: "adopting a restrictive policy towards warfarin use in ESRD seems wise, such as reserving it for patients with a CHADS score greater than 2". The use of the CHADS score to stratify dialysis patients with AF has been addressed in a study in this month's Kidney International, and the results suggest that even this restrictive approach may not be safe.
Briefly, CHADS2 is a risk score that stratifies members of the general population with AF by stroke risk, in order to permit informed clinical decision-making regarding the risks/benefits of warfarin anticoagulation. Its name is an acronym derived from the component independent stroke risk factors, namely Congestive heart failure, Hypertension, Age over 75 years, Diabetic status, and history of Stroke (or TIA). This study highlights several caveats regarding the use of CHADS2 (and warfarin use in general) in the dialysis population, information you’ll need next time you’re thrashing out this thorny issue with your Cardiology colleagues.
The authors examined 17,500 dialysis patients from the international DOPPS study, among whom the prevalence of AF was 12% and the incidence of new-onset AF was 1 case per 100 patient years.


  1. CHADS2 divides this representative sample of dialysis patients 50:50 into high ( greater than 4 per 100 pt-yrs) and low (less than 2) risk for stroke. 
  2. In the low-risk group, the risk of stroke equals the rate below which anticoagulation is not recommended for AF in the general population and, as such, would support a decision not to anticoagulate a dialysis patient with AF and a low CHADS2 score. 
  3. Two key components of the CHADS2 score, HTN and heart failure, did not independently predict stroke in this study. As a result, CHADS2 may overcall stroke risk in some low-risk HD patients, and caution should be exercised when calling a patient high risk based on these 2 conditions. A dialysis-specific CHADS score that drops hypertension and heart failure would likely improve its discriminatory power, but requires further study. 
  4. Warfarin anticoagulation did not reduce stroke risk in this study. In fact, there was a strong tendency to more frequent cerebrovascular events, particularly in the elderly. Whether this surprising finding was caused by a direct effect of warfarin on the rate of hemorrhagic stroke, or that patients who were prescribed warfarin were already an inherently high-risk group, the fact remains that one needs to be very cautious when prescribing anticoagulation to these patients. It would appear that in some patients identifyed as being at higher stroke risk (particularly older patients), the risks of anticoagulation still outweigh the benefits. 
The upshot of this study is that CHADS2 appears to function adequately in identifying patients at low-risk for stroke, and provides support to a clinical decision to withhold warfarin in that context. However, its ability to identify high-risk patients suitable for anticoagulation is highly questionable, as 3 of its 5 component factors (HTN, heart failure and possibly age) perform poorly in the dialysis population. How to approach the issue of anticoagulation in such patients remains a gray area.

Tuesday, June 8, 2010

Does CMV glomerulopathy exist?

I asked this question during my clinical renal fellowship at Brigham, where I had the chance to take care of a 39 yo female with a history of ESRD secondary to MPGN s/p DCD kidney transplant 8 months ago from CMV positive donor, she was CMV negative. She developed CMV disease, was treated with IV Ganciclovir with significant improvement, was switched to Valcyte 900 BID than switched to 450 BID. She was taken off her Valcyte by an outside nephrologist for decreased WBC. Her viral load increased and she was started again on Valcyte. She presented with low grade fever, neutopenia and and an elevated creatinine to 1.8 mg/dl from a baseline of 1,2 mg/dl. Her CMV viral load increased and it was obvious that we are dealing with resistant CMV disease. Interestingly, her kidney biopsy showed CMV inclusions in the epithelial and endothelial cells with no interstitial nephritis.
I reviewed the literature for CMV glomerulopathy at that point.

Dr. Rubin from MGH described the first cases in 5 our of 14 renal allograft recipients during clinically manifest viremic CMV infection, with little or no tubulointerstitial changes.
The characteristics of this glomerulopathy are:
  • Endothelial cell hypertrophy or necrosis
  • Narrowing or obliteration of capillary lumens
  • Fibrillar deposits in glomerular capillaries
  • Mild segmental hypercelbularity
  • Mononuclear cell infiltration without tubular changes
  • IF revealed deposition of IgG, IgM, and C3 along the glomerular basement membrane and within the mesangium
  • One specimen, anti-CMV antibody staining was observed within glomerular capillaries
  • No viral inclusions were found on EM.

Others reported different types of lesions like cryoglobulinemic necrotizing GN or immunotactoid glomerulopathy. The association in those cases were made based on temporal relationship between the appearance of CMV antigenemia and the lesion.

The existence of this CMV-associated glomerulopathy described by Dr. Rubin has been questioned, however, by Herrara et al. Kidney Int 1986, who studied four different groups of immunocompromised patients with CMV infection, including seven with renal allograft dysfunction. In all seven patients, biopsy specimens demonstrated glomerular pathology similar to the changes described by Dr. Rubins’s group at MGH. Nevertheless, IF failed to show anti-CMV antibody deposition. In addition, no viral particles were detected on EM.

The authors suggested that the glomerular changes represented a form of acute transplant gbomerulopathy resulting from antiendothelial antibody injury or a protracted, early, or unresolved form of acute vascular rejection. Furthermore, Harmon et al. showed that this glomerulopathy occurred in only seven of 56 renal allograft recipients with a clinical diagnosis of CMV disease. Three of the seven patients with this lesion were not even viremic. Anderson et al., using immunohistochemistry and in situ hybridization on 15 biopsy specimens from viremic renal allograft recipients with glomerulopathy, found no evidence of CMV antigens or DNA.

Our case is different because there are viral inclusions in the epithelial but also in the endothelial cells with some swelling noticed by our famous pathologist. There was no associated glomerular inflammation and C4d staining was negative. The lesion was called CMV glomerulitis but it is obviously different from the CMV glomerulopathy described by Dr. Rubin in his NEJM paper. Patient was treated with Cidofovir. Her creatinine improved to baseline and her lesions improved on a subsequent follow up kidney biopsy. Since than, many reports described the same lesions associated with CMV infection, including a
report in AJKD. The CMV glomerulitis similar to our case progressed to collapsing FSGS. The lack of proteinuria before transplantation supported the contention that the collapsing glomerulopathy arose de novo rather than being recurrent.


I think we have enough evidence that CMV glomerulitis exist. The bottom line remains how to prevent the disease, prevent resistance and be aware of the deleterious effects of underdosing like in this case.

Monday, June 7, 2010

Race and the prediction of GFR by MDRD

The 4 variable MDRD equation was developed based on a US sample of 1628 participants in which glomerular filtration rate was measured as the renal clearance of I-iothalamate and a prediction equation was formulated using serum creatinine, age, sex, and race. For black race, the answer is multiplied by 1.2.

My question is, how well does the MDRD equation predict GFR in different global populations?

Two studies performed in sub-Saharan Africa (Ghana N=944 and South Africa N=100) comparing the MDRD and Cockcroft-Gault (CG) estimates of glomerular filtration rate (GFR) against measured creatinine clearance (24 hour urine creatinine and clearance of chromium-51-EDTA) showed that the MDRD equation performed better without using the ethnicity factor of 1.2. In a small Saudi study (N=32), GFR estimated by MDRD revealed the strongest correlation with the measured inulin clearance (r= 0.976, P= 0.0000). The correlation between eGFR and Clearance of inulin in a Japanese population (N=248) was better with the 0.881xMDRD equation than with the 1.0xMDRD study equation.

Clearly the prediction of GFR by MDRD varies by global region and most likely this variability correlates with genetic/environmental factors contributing to body muscle mass.

Board question: Hypertension-1 answer



The best answer is D.



Lifton et al. described a single gene mutation on the hormone-binding domain of the mineralocorticoid receptor (MCR). Individuals with this missense mutation develop early-onset hypertension with characteristic low renin and aldosterone levels. The mutation causes the MCR to be constitutively active, regardless of aldosterone levels, and transforms the MCR so that steroid hormones that are typically antagonistic become agonistic (in particular, progesterone and cortisone).

During pregnancy, when progesterone levels increase 100-fold, the MCR becomes hyperactive and leads to sodium reabsorption and potassium secretion via the principal cell of the distal collecting tubule (Figure above). The avid sodium retention and volume expansion appropriately suppress renin and aldosterone levels. This condition is not associated with proteinuria, edema, or neurologic changes, which distinguishes it from pre-eclampsia.

Given the low levels of aldosterone, this condition is refractory to standard medical therapy aimed at reducing aldosterone levels through RAAS blockade. In fact, mineralocorticoid receptor antagonists can actually exacerbate hypertension in this condition! Delivery of the fetus may be necessary to treat severe, refractory hypertension during pregnancy.

Essential hypertension results from a complex interplay of both genetic and environmental influences. Uncommonly, an isolated genetic mutation can engender hypertension, like in this case. These monogenic forms of hypertension affect either electrolyte transport in the distal nephron, or the synthesis and/or activity of mineralocorticoids, leading to a common final pathway of increased distal tubular reabsorption of sodium and chloride, volume expansion, and hypertension.

Other low renin, monogenic forms of hypertension include:
  • Familial Hyperaldosteronism Type 1 (aka, glucocorticoid-remediable aldosteronism)
  • Familial Hyperaldosteronism Type II
  • Syndrome of apparent mineralocorticoid excess
  • Liddle syndrome
  • Pseudohypoaldosteronism type II (aka, Gordon syndrome)
  • Congenital Adrenal Hyperplasia

They provide excellent fodder for any number of board-style questions!

Michael Lattanzio DO

Thursday, June 3, 2010

Board question of the week: Hypertension-1

A 26-year-old primigravid woman is admitted during her 34th week of pregnancy with severe, refractory hypertension. She was noted to have mild hypertension prior to pregnancy. Her family history is remarkable for pregnancy-related hypertension in her aunt. Her blood pressure decreased early in the course of the pregnancy, but then rose dramatically, reaching 170/100 mmHg at 29 weeks despite antihypertensive therapy. She denies any edema or neurologic changes.

Her chemistries are listed below:

Na-143 K-3.6 Cl-110 HCO3-28 BUN-8 Creat-0.5 Uric Acid-3

Urinalysis negative for blood and protein

Urine electrolytes:

Urine sodium 20 meq/L, Urine potassium 75meq/L

Renin and Aldosterone level were both suppressed

Due to worsening blood pressure, a Caesarian section was performed, and the patient delivered a healthy baby girl. Her blood pressure control stabilized shortly after delivery.


The answer and explanation will be posted on Monday July 7th

Michael Lattanzio DO

*RFN board questions are meant to help introduce concepts about nephrology related diseases and do not represent actual questions seen on the ABIM exam.

It's all about the lemon juice...

At Renal Grand Rounds last week one of our fellows, Dr. Martina McGrath, presented the case of a 53 year old male with no past medical history, who initially presented with fever, chills, chest pain and epistaxis, was diagnosed with acute pericarditis and was noted to be pancytopenic. Further workup and ultimately bone marrow biopsy was diagnostic for AML and he was transferred to our tertiary care hospital to commence induction chemotherapy.

His course was remarkable for pericarditis and tamponade necessitating pericardial drain placement. After a repeat bone marrow biopsy was complicated by large pelvic hematoma he developed transfusion dependent anemia, necessitating more than 10 units of PRBCs. Unfortunately, he developed worsening bilateral pulmonary infiltrates necessitating BiPAP support and total body ECF volume overload ensued. This necessitated daily furosemide to control his volume overload.

A renal consult was called because he developed metabolic alkalosis with the following laboratory results:

Na-126 K-5.0 Cl-87 CO2-38 BUN-17 Creat-0.58 Glucose-119

Ca-8.4 Phos-2.6 Urate-2.8 Alb-2.8

ABG:pH-7.53 pO2-67 pCO2-48

ALT-61 AST-52 Alk phos-150

Hgb-8 Hct-25 WBC-7.5 Plts-28

The chest xray showed severe bilateral airspace disease consistent with pulmonary edema.

What is the acid base abnormality and why?

It is clear that this patient had metabolic alkalosis with relatively appropriate respiratory compensation, depending on how closely correlated these laboratory tests are in time.

Metabolic alkalosis is a relatively common clinical problem, most often induced by diuretic therapy, or the loss of gastric secretions due to vomiting or nasogastric suction.

Two separate abnormalities can contribute to metabolic alkalosis:
  1. An elevation in the plasma bicarbonate concentration due to hydrogen loss in the urine or gastrointestinal tract, hydrogen movement into the cells, the administration of bicarbonate, and contraction alkalosis.
  2. A decrease in net renal bicarbonate excretion.
In this patient, contraction alkalosis and loss of chloride and hydrogen ions in the urine due to diuretic therapy was certainly a contributor. However, another important consideration was his exposure to a large amount of bicarbonate infused into his body in the form of citrate, given normal liver function. We often forget about iatrogenic factors in our patients, but in this case, his multiple blood transfusions were certainly an important source of citrate/bicarbonate.

Metabolic alkalosis has been described:
  • The infusion of more than eight units of bank blood (anticoagulated with citrate).
  • Observed when citrate rather than heparin was used as an anticoagulant in hemodialysis
  • Continuous renal replacement therapy (CVVHD) with citrate.
  • Extensive use of crack cocaine (which contains significant amounts of an alkali) in dialysis patients.
  • Fresh frozen plasma as a replacement fluid during plasmapheresis.

Wednesday, June 2, 2010

Amazing Immunology!

I am still reviewing all my notes from the American Transplant Congress that occurred last May in sunny San Diego but I wanted to share with you a couple of interesting findings that I learned:

First of all, the importance of alloantibodies in chronic rejection is becoming even more evident. C4d staining has emerged in multiple studies presented as an insensitive marker of this lesion on allografts. However, we still don’t have any better marker. Some promising results came from analyzing gene expression for endothelial markers of activation by the group from Dr Halloran (Canada). Further validation of these findings are still ongoing, including the evaluation if other lesions not related to alloantibodies could also upregulate those genes.

Second, agents that could potentially block the alloantibody toxicity to the endothelium are now being studied in phase II clinical trials. A great drug seems to be Eculizumab that was shown to decrease acute humoral rejection without affecting donor specific antibody levels by blocking the final step of activation of the complement pathway.

Third, among the 3 forms of techniques to detect alloantibody, a positive cytotoxicity assay (CDC) was shown to correlate with worse allograft outcomes compared to more sensitive methods like flow cytometry and luminex, reinforcing the importance of the old-fashion test.

Lastly, the importance of memory T cells in long-term allograft survival is emerging. These T cells have very interesting properties: they have a higher efficiency in mounting a response, do not need any costimulation and have a lower threshold for activation. Some newer agents targeting CD2 and LFA1, dominant markers of memory T cells, have shown some promising data in animal models.

Maybe we should be listen to Einstein now: "Make everything as simple as possible, but not simpler."

Nephrology board prep

The results are in. Looks like the best way to study for the nephrology board exam, scheduled to be given on November 4th, 2010, is the ASN Board Review Course. I personally did not attend this course last year, but I did hear very good things about it. Comments from a course attendee- "it was focused, organized and worth the money". By no means is this course cheap. For fellows-in-training it cost $975 to register for the week long course (held August 28th-September 3rd, 2010). Not to mention the plane ticket to San Francisco and "special" hotel rate of $234 a day. Adding in miscellaneous costs (food, taxi etc) and this trip could cost you well over $2800. Add this to the outrageous fee of $2060 to take the nephrology boards and you can see why you don't want to take this test twice. So, for anyone interested, prepare to shell out $2,800.
Maybe some of the fellows or attendings can chime in on what they think about the ASN review course.

Next, in second place is the Brigham Renal Board Review Course (combined DVD and in-person). This is a 5 day course held in Boston, MA, August 9-13, 2010. Tuition is $695 and the Hotel rate is 119/night. I've also heard great things about this course. Personally, I did not attend this course, but instead purchased the DVD. Total Cost of Course- $2,000. The DVD's can be purchased for $1500. I found these useful especially the acid base and fluid/electrolyte sections.

Coming in third is Comprehensive Clinical Nephrology. Pictured to the left is the cover of the much awaited 4th edition taken from the Elsevier website scheduled to be released in September of 2010. My study group (consisting of 4 fellows) used the 3rd edition to prepare for last years exam. We started going through the text a few weeks after the in-service exam results were released (in early June) and finished in late September. The group met once every two weeks. We would each summarize 2-3 chapters at the bi-weekly meeting. So, we would go through about 8-10 chapters every 2 weeks allowing us to finish the entire book in 10 or so meetings (101 chapters). Overall, I think this method is difficult to achieve by oneself as the book is rather cumbersome. It really takes a group approach to get through this. Bottom line, this is a great textbook and something every fellow should have. I would only try using this book for board prep if you have a dedicated group.
Cost- $200.



Coming in at a tie for fourth is Renal Fellow Network and NephSAP. The RFN site and other popular nephrology specific websites (Uremic Frost, Nephron Power, Precious Bodily Fluids, Nephrology On Demand) have become an increasingly popular way to get relevant and easily digestible information. RFN has over 600 topics currently cataloged. I used renal fellow network extensively and thought it was a great way to read about interesting topics. We hope to continue this for years to come. Cost- Free


NephSAP was probably the most disappointing series from a board prep perspective in my view. To me, NephSAP is very detail oriented with much of the focus is on "cutting edge" research. The text was not helpful, in my opinion, for high yield study prep. However, you can access the online version of the exam questions which are worth reading a few weeks prior to the exam.
Cost- Free for fellows with the complimentary fellow ASN membership


Lastly, I included a few other options like UpToDate, The NKF Primer on Kidney Disease, Burton Rose- Acid Base and Journal Review Articles. Each of these can be useful study tools. Nate has already commented on the utility of Burton Rose-Acid Base which I would completely agree with. Interestingly, it seems that many institutions are forgoing their subscription to UpToDate secondary to cost. To purchase this on your own it will cost $195 for a trainee and $495 for a non-trainee (1-year). The Primer might be a better way to study as it is more concise than Comprehensive Clinical Nephrology. Maybe someone can comment on this.


In conclusion, I was a little disappointed with the study prep options available for the nephrology ABIM subspecialty exam. Especially with the multitude of options available for the Internal Medicine exam. My main problem was the lack of good question banks that are specifically geared for Nephrology. NephSAP provides a few, but this was hardly enough. The MKSAP nephrology section questions are a little to broad and frankly do not go into enough detail that a nephrology fellow needs. This is not, by any means, a comprehensive list of study options. I welcome any other options that I didn't include. A quick google search on this topic yields very little information. Good luck to anyone studying for the exam. My best piece of advice, "devise a plan early and stick to it".

Tuesday, June 1, 2010

Something about this doesn't seem quite right...

There was an interesting case report in KI earlier this year. It concerned a 69yr old man with a history of benign prostatic hyperplasia and Waldenstrom’s Macroglobulinemia (WM) who was admitted for the workup of renal failure. His creatinine had been noted to be 4.8 mg/dl at a routine visit. He was asymptomatic and normotensive and he denied taking any nephrotoxic medications. Apart from a raised serum protein and IgM fraction, his other bloods were normal including his BUN. He did have 1.1g/24hrs proteinuria but no hematuria. A renal ultrasound showed bilateral hydronephrosis that was thought to be related to the BPH, and as a result, bilateral pigtail stents were placed and he was commenced on iv fluids.


Over the next few days, his serum creatinine did not improve significantly and he underwent a renal biopsy. This showed nephrosclerosis, tubular atrophy and mild interstitial fibrosis with 10/15 glomeruli appearing completely normal. Immunofluorescence was also normal. The findings on renal biopsy did not correlate with his serum creatinine level.


In the Jaffé reaction, creatinine reacts with picric acid to form a colored complex. This forms the basis for the commonest methods for measuring serum creatinine. However, this test has well known limitations. Under normal circumstances, the Jaffé reaction overestimates the serum creatinine concentration by 10-20% because of the presence of endogenous chromogens. These chromogens include acetone and acetoacetate which, in the case of diabetic ketoacidosis, can lead to a significant overestimation of the serum creatinine. Similarly, certain drugs, including cephalosporins, flucytosine and barbiturates, can interfere with the assay.


Recently, more specific enzymatic assays have been developed which are thought to be less susceptible to falsely high readings. These involve measuring the generation of ammonia when creatinine is hydrolyzed.


In the case above, pseudohypercreatininemia was suspected because the biopsy results did not match the serum creatinine. The hospital was using an enzymatic method for measuring the creatinine concentration. When the patient’s serum cystatin C was checked, it was found to be only slightly elevated and his serum creatinine by the Jaffé method was only 1.0 mg/dl. This is the third reported case of pseudohypercreatininemia in a patient with WM where the enzymatic method was used to determine the serum creatinine. The mechanism for the false reading is uncertain but it may be related to increased turbidity or binding of the Ig to the enzyme.


This case shows the limitations of the test for serum creatinine but also demonstrates the importance of knowing which test is used in your own institution. And if you do see a patient with an isolated creatinine elevation, think of pseudohypercreatininemia as a cause.


Posted by Gearoid McMahon MD