The Nephrologist as Team Leader

Within the last 2 years dialysis facilities in the US have been adjusting to the now not-so-new Center for Medicare & Medicaid Services (CMS) Conditions of Coverage. CMS, as many of you know, funds the ESRD program to the tune of many billions of dollars and as such gets to set some of the rules, known as "Conditions of Coverage". These rules are designed to ensure quality of service from their perspective. Auditors acting on behalf of CMS periodically survey dialysis facilities in a rigorous fashion and may (and often do) issue citations and conditional warnings as result.
In order to prepare for the eventuality of one of these surveys, I received a memo this week with a reminder of my responsibilities as the Hemodialysis Unit Medical Director:
"By virtue of the Medical Director's leadership of the facility's Governing Body, his/her responsibilities extend beyond the primary focus on improving quality of care delivered in the facility and extends to the general management and operations of the facility. As such, all condition level citations are linked to /and are the responsibility of the Medical Director according to CMS".
It went on to append a summary of findings from recent audits, occurring in a particular geographical region, identifying some of the deficiencies which have been noted by the auditors as citable or worthy of a conditional warning. Here are a few of them:


Infection control standards not met due to: 

- Patients not washing and sanitizing their hands pre and post treatment 

- Staff members accessing computer terminals with gloves on after patient contact 

- Patients self holding needle access sites post treatment without gloves on 



Physical environment standards not met due to: 

- Unsanitary and non working sinks and faucets 

- Open boxes of needles and syringes not properly stored 



Documentation requirements not met due to: 

- Incomplete Interdisciplinary Team assessments 

- Medical records not stored properly 

- Peritoneal dialysis orders incompletely and improperly written. 



What does this all mean? At first glance these citations/conditions may seem to be out of the realm of the practicing clinician whose focus is elsewhere, but in actuality they are integral to the proper care of our patients and the infection control lapses certainly should raise a high level of concern. We all have a natural disinclination to being surveyed but maybe these surveys are useful if they encourage us to put into place processes which ensure these lapses do not occur and if we develop systems of self assessment and quality improvement within our domain of responsibility.

Which brings me to the point of this blog. It's all about the team, and as Physicians we assume a natural leadership role when we deliver care to our patients and some of us are eventually appointed to leadership positions as our career advances. The usual dialysis unit personnel resources include Nurses, Patient Care Technologists, Dieticians, Social Workers and Administrative Staff. CMS is telling us we are responsible for the performance of this team on multiple levels. Traditionally our training has not focused much attention on preparing us for such leadership. But, the ability to develop and lead a team in the delivery of care to a defined patient population such as an office practice or a dialysis facility may be as important as an extensive clinical knowledge base in terms of improving outcomes. Being able to function as a clinician and a team leader is a challenge and interestingly many of the leadership skills we eventually acquired are done so by osmosis and without direct teaching.

For those interested the Medicare and Medicaid Programs; Conditions for Coverage for End-Stage Renal Disease Facilities; Final Rule can be found in the Federal Register / Vol. 73, No. 73 / Tuesday, April 15, 2008 / Rules and Regulations. It is ~ 120 pages but is worth reviewing if you are planning career involving outpatient dialysis care.


Posted by David Steele M.D.

HCG in Kidney Disease

That cardiac biomarkers, including Troponin and BNP, can be elevated in CKD or ESKD without necessarily having clinical significance is familiar to most of us. Whether you believe that an elevated Troponin in ESKD is due to diminished clearance or some constant low-level myocardial damage of unclear significance, most would be comfortable dismissing borderline positive results without suggestive signs or symptoms.

Recently I was asked an interesting question pertaining to pregnancy testing in CKD and ESKD. A dialysis patient had a serum HCG level that was borderline positive. The patient and her physicians wanted to know whether this could be a false positive related to her kidney disease or whether she may in fact be in the first weeks of a pregnancy. After searching the literature and conferring with my OB colleagues, here is what I found:

Here is a case report and a nice review of the topic. Not surprisingly HCG levels can be falsely elevated in CKD, though for quite a variety of reasons. These include decreased clearance of HCG, increased levels of other gonadotropins that cross react with the HCG assay, including LH and FSH, as well as other cross-reacting substances including cold agglutinins and heterophile antibodies.

How to distinguish? The urine HCG assay does not cross-react with these substances, and so, if the patient still makes urine, confirmatory testing with urine HCG is a reasonable first step. In ESKD patients who no longer make urine, progesterone levels can be used as a next step especially when more immediate knowledge of pregnancy status is required. If progesterone is low, viable pregnancy is unlikely, though serial serum HCG levels should be monitored to rule out non-viable pregnancy (egs, ectopic). If there is no urgency to determining pregnancy status, follow-up serum HCG to see if doubling occurs at expected intervals should be performed. In my patient's case, her serum HCG level one week later was the same as that one week prior, and the serum HCG was deemed to be elevated due to decreased clearance in ESKD.

Don't forget to look for proteinuria!

At Renal Grand Rounds yesterday, we discussed the case of a previously healthy 50 year old man who presented with fulminant hepatic failure and AKI. He was initially thought to have AKI related to either SIRS/hypotension or Hepatorenal Syndrome (which should be a diagnosis of exclusion), but was astutely noted to have significant (about 6 gm/day) proteinuria. The patient was worked up further: his serum electrophoresis revealed a monoclonal immunoglobulin spike and urine Bence Jones protein was present. Serum free kappa light chains were high and the kappa to lambda light chain ratio was significantly elevated. Concomitant liver biopsy revealed AL amyloidosis, which was further confirmed and typed by fat pad and colon biopsies. Unfortunately, the patient succumbed to multi-organ failure.

The teaching point from this case is that the proteinuria was the key to making the correct diagnosis.

By way of quick review, amyloidosis is a group of diseases characterized by extracellular deposition of beta sheet fibrils which, in systemic forms, cause progressive organ dysfunction.

AL amyloidosis is characterized by fibrils that contain fragments of the variable portion of monoclonal light chains. This is the result of a clonal expansion of plasma cells, but interestingly, most patients with AL amyloidosis do not develop the manifestations of multiple myeloma, and most multiple myeloma patients do not have amyloid deposition. What both diseases have in common, however, is renal dysfunction which presents with significant proteinuria. Of note, given the pathophysiology of these diseases, the proteinuria is not related to albuminuria. Therefore, it is important to obtain a spot protein to creatinine ratio on all patients who may have otherwise unexplained or difficult to explain AKI, and subsequently pursue further work-up, including free serum light chain measurement.

In AL amyloidosis, response to therapy correlates with reduction in circulating light chains, so a hematologic response is the first marker in anticipation of renal function recovery or improvement. Interestingly, as well, the degree of baseline proteinuria on presentation correlates with response to treatment. Current treatment options include melphalan (an alkylating agent) plus steroids, Velcade (Bortezomib, a proteasome inhibitor) and rescue stem cell transplantation, which remains controversial.

Endocrine and thiazide-induced hyponatremia

We have all been taught that before making the diagnosis of SIADH, we have to ensure that the patient has normal adrenal and thyroid axes. Why is this so important and how do thyroid and adrenal dysfunction cause hyponatraemia?


The mechanism in hypothyroidism is incompletely understood, but felt to relate mainly to a reduction in cardiac output, increased activity of baroreceptors and subsequent non-osmotic release of ADH. Often, a reduction in GFR is noted in hypothyroid patients, thereby reducing the quantity of free water that reaches the distal nephron. Correction can be achieved by the administration of exogenous thyroid hormone.
In adrenal insufficiency, the reduction in cortisol may cause reduced cardiac output and blood pressure, again via a poorly understood mechanism. This can result in non-osmotic ADH release and tendency towards free water retention. Perhaps more importantly, ADH release from the posterior pituitary is under the control of CRH from the hypothalamus. CRH in turn is under negative feedback control from cortisol. So, in states of low cortisol, the negative feedback on CRH is lost and, in turn, ADH release is stimulated.


Why do thiazides cause more hyponatraemia than loop diuretics?
The efficacy of ADH depends on the generation of the medullary concentration gradient via NaCl reabsorption, without water, in the thick ascending limb of the loop of Henle. This creates a gradient for water reabsorption via aquaporin-2 insertion in the luminal membranes of the cortical and outer medullary collecting tubules.
With this in mind, it becomes clearer why thiazide diuretics are more likely to cause hyponatraemia than loop diuretics. Loop diuretics, by inhibiting the sodium reabsorption in the thick ascending limb of Henle’s loop, interfere with the generation of the hypertonic medullary interstitium; so, despite inducing a mild increase in ADH secondary to volume depletion, the ADH is less effective because there is a reduced concentration gradient for water reabsorption. Thiazide diuretics act on the distal tubule, having no effect on the medullary concentration gradient, thereby allowing ADH induced by volume depletion to promote water reabsorption unabated.


Posted by Finnian McCausland M.D.

VEGF inhibitors and proteinuria

I've recently had the privilege of caring for a patient undergoing chemotherapy for a metastatic malignancy using agents targeting the vascular endothelial growth factor (VEGF) pathway. This patient, having tolerated three cycles of avastin and ipilumimab without any complications, was found on routine screening by his oncologist to have >1g/day of proteinuria and was thus referred to us for further evaluation. He was seen in our clinic two weeks later, at which time he was feeling generally well and had no gross abnormalities on physical exam (normal volume status, normal cardiac and pulmonary exams, no peripheral edema). His serum BUN and creatinine were both normal, a urine protein to creatinine ratio revealed essentially no proteinuria, and his urine sediment was bland without any cellular casts. We were, of course, pleasantly surprised. On the basis of these findings, we decided that the most likely etiology of the transient proteinuria was the VEGF inhibitor, and that it was less likely that he had developed a de novo renal disease. We informed our patient and his oncologist that they could continue with the prescribed treatment regimen, and that we should continue to observe him closely for any subsequent development of renal abnormalities.

There is a documented association between VEGF inhibitors (e.g. bevacizumab, sunitinib, sorafenib, pazopanib, axitinib) and renal disease. While these agents are usually well tolerated, their toxic effects include proteinuria and hypertension. The incidence of proteinuria has been variable in different studies depending on patient characteristics, cancer type, and signals targeted, though a number of clinical studies report that treatment with bevacizumab (avastin) may be associated with increased proteinuria. For instance, bevacizumab has been associated with proteinuria in 23-38% of patients treated for colorectal cancer and in up to 64% of patients treated for renal cell carcinoma. One meta-analysis of RCTs with patients receiving bevacizumab reports a relative risk of 1.4 for proteinuria at a low dose (2.5 to 7.5 g/kg) and 1.6 for a high dose (10 to 15 mg/kg) of bevacizumab. Proteinuria appears to at least partly resolve with discontinuation of the VEGF inhibitor, though some patients are able to resume therapy without an increase in proteinuria. It is not clear at this time whether there is an association between duration of treatment and the development of proteinuria.

Renal biopsy may be indicated in patients with metastatic cancer and proteinuria with evidence of worsening kidney disease, unexplained acute kidney injury, or nephritic syndrome. Among patients who have undergone renal biopsy for proteinuria associated with VEGF inhibitors, the most common pathological finding is thrombotic microangiopathy, though other conditions including:

• Collapsing glomerulopathy
• Cryoglobulinemic glomerlonephritis
• Immune complex-associated focal proliferative GN
• Sorafenib-induced acute interstitial nephritis

Currently, there are no evidence-based recommendations for how to specifically treat proteinuria caused by VEGF inhibitors. However, it is reasonable to try conservative treatments such as ACE inhibitors or angiotensin-receptor blockers, particularly in patients with both proteinuria and hypertension.

Of note, this topic of nephrotoxicity associated with VEGF inhibitors has recently made it to the nephrology boards!

A trap for angiotensin type 1 receptors

The renin-angiotensin system is powerful regulator of blood pressure homeostasis. An article published in the March 24 issue of JASN highlights an emerging area of research into the modulation of AT1 receptors on different tissues.

The majority of well-known angiotensin II actions are mediated via AT1 receptor stimulation, and angiotensin converting enzyme inhibitors (ACEi) and AT1 receptor blockers (ARBs) have been widely used as antihypertensive agents with cardiovascular protective effects. Elucidating factors that regulate AT1 receptor expression levels in different tissue compartments will hopefully lead to novel agents to treat hypertension and its associated end-organ damage (ESRD, CHF and Stroke). Recent studies have demonstrated the existence of several proteins interacting with AT1 receptors that may modulate AT1 receptor expression level, sensitivity and internalization. A recent review article highlights this emerging field. Atrap (AT1 receptor-associated protein) is the best characterized protein and the focus of the March 24 article by Oppermann et al.

It was previously reported that Atrap (a 19kD protein) interacts specifically with the carboxyl-terminal domain of the A1a receptor and catalyzes its internalization in cultured cells. Prior in vivo studies over-expressing the Atrap protein in the heart, aortae and femoral artery in mice demonstrated a protective effect in these tissues in response to angiotensin II infusion. Overall, the prevailing literature suggested an inhibitory or protective effect of Atrap on AT1 receptor function. This group knocked out the Atrap gene in mice to test this hypothesis in vivo.

They reported that Atrap KO mice have a higher resting blood pressure (by 10 mmHg) as measured by radiotelemety. Suggesting that Atrap is important in regulating basal blood pressure and that its absence leads to systemic hypertension. Interestingly, they found that Atrap is highly expressed in the kidney (then testis=adrenal>heart>lung=liver=aorta=brain). Specifically, they showed that Atrap is highly expressed in the proximal tubule of the kidney. Previous investigations have focused on the distal tubule as potential sites that affect blood pressure as most of the known genetic mutations in sodium transport causing hyper/hypotension are linked to the distal nephron (Bartter, Little, Gitelman syndromes, etc). This group reports that Atrap KO mice have more AT1 receptors in the proximal tubule which allows for increased angII-dependent NHE-3 activity causing volume expansion and hypertension.

This highlights the importance of investigating novel pathways regulating the renin-angiotensin system. Modulation of this system with the use of ACEi, ARBs and now direct renin inhibitors have continued to be the mainstay of therapy for patients with heart failure, diabetes, hypertension and kidney disease. Activation of Atrap may be more specific and more physiological for inhibition of At1 receptor signaling. New drug discovery modulating Atrap protein expression could lead to novel therapy. For now, much more research is needed.

Mythbusters: Hypertension

It seems like there have been a lot of recent developments in the management of hypertension, and several sacred cows have become burgermeat. I thought I'd summarize a few of these important developments here:

1. Blood pressure targets in the over 80's
The Hypertension in the Very Elderly (HYVET) trial taught us that treating hypertension in the very elderly is effective in preventing stroke. However, we may have been over-treating the "oldest-olds" for years, and that target SBPs for this group should be< 150/80mmHg according to a recent Cochrane review. As nephrologists, we may have been particularly culpable, due inappropriate application of a 130/80 mmHg target for elderly patients with mild reductions in GFR ("CKD").

2. Who benefits from aldosterone blockade?
A strong association has been demonstrated between abdominal obesity, sleep apnea and aldosterone excess, such that it has been suggested that visceral fat may be a source of aldosterone, contributing to resistant hypertension in the abdominally obese. Recently, spironolactone has been shown to be effective in managing resistant hypertension in the abdominally obese, so keep it in mind.

3. The white-coat effect and BP variability
Reassuring patients who appear to only have spikes of hypertension when they come to see you in the clinic may be the wrong thing to do. This recent Lancet article suggests that variability in BP, and spikes of hypertension in particular, may in fact be more dangerous than sustained hypertension. An approach to managing this problem is to avoid agents known to increase BP variability, such as beta blockers. Furthermore, patients who believe that it's okay for their BP to be elevated because they have recently been active need to be educated that this is incorrect.

4. Allopurinol for hypertension
Urate is periodically in and out of vogue as an instigator / perpetuator of kidney disease and hypertension. I personally believe it to be a marker of oxidative stress, but am still undecided about it having a direct role in kidney disease and progression. I have treated severe hyperuricemia in CKD patients with this specific intention / hope of attenuating disease. This recent JAMA paper suggests this approach is not complete madness. This short-term crossover study of adolescents with hypertension and hyperuricemia found that allopurinol 200mg bid controlled hypertension on it's own in 66% of patients. Another one to keep in mind

That's enough for today, I'll return to this topic next time.

World Kidney Day 2010

Happy World Kidney Day! Celebrated every year in March, World Kidney Day is a day devoted to raising awareness of kidney disease across the globe. This year promised to be a huge success: cities throughout the world, from Bahrain to Belgium, held kidney awareness events, and celebrities such as Tom Hanks and French President Nicolas Sarkozy jumped on the kidney awareness bandwagon to lend their support to the cause. Besides raising awareness of our “amazing kidneys”, the day’s objectives were to encourage screening for CKD, recognize the importance of risk factors in the development of kidney disease, and encourage preventive behaviors. This year’s theme was “Protect Your Kidneys: Control Diabetes,” in order to place special emphasis on the growing prevalence of diabetic renal disease.

Tackling the problem of CKD is no small job. The last NHANES survey in 2009 estimates the U.S. prevalence of CKD stage II-V at 13%. While less prevalent in the developing world, CKD is expected to become a much greater problem due to the rapidly increasing rates of diabetes (an 85% increase in Central and South America, and 75% in the Western Pacific region, by 2025), not to mention hypertension. CKD has far-reaching effects on patient outcomes: for Medicare CKD patients in 2009, adjusted all-cause hospitalization rates were 1.5 times the non-CKD population, and all-cause mortality was twice as high as in non-CKD patients, even when adjusted for comorbid conditions. Then there is cost: in one article by DH Smith et al in 2004, the management of CKD alone was estimated to cost an additional $8000 annually per patient.

The renal fellows at Brigham and Women’s Hospital spent the day running a screening booth in the hospital lobby, helping to advise patients on blood pressure control, urinalysis results, and diabetes testing. Whether your clinic was able to hold screenings, pass out pamphlets on kidney health, or spend an extra minute counseling patients on kidney disease prevention, it is even more critical to continue the efforts in the year to come. Hopefully we can reverse the alarming increase in CKD prevalence throughout the world and—it is to be hoped, in the best possible way—put some of us out of business.

Lack of respect for the beans

I have just learned two very interesting aspects of kidney donation that I would like to share with you. As part of my transplant fellowship, I am required to participate in the decisions about accepting or not a kidney from a deceased donor and to join the surgical team during organ procurement.

Despite a list of absolute contraindications which include donors with active malignancy, untreated sepsis or active intravenous drug abuse, I have found that the limits are a little more subjective than expected, and with the organ shortage, transplant services are even more aggressive of using organs labeled as expanded criteria donor (ECD).

We had an interesting donor offer recently, in which a young female had died after a closed head trauma complicated by disseminated intravascular coagulation. The creatinine was normal and urine output was around 40cc/hour. Our transplant service decided to accept both kidneys. Not sure if you guys know, but the kidneys are actually the last organ to be removed from the deceased donor!? Liver, heart and lungs have preference!!! We had to wait almost 2 hours for another team to take out the liver before we were able to get to the beans… The concern was: could the DIC had damaged the kidneys?
DIC is associated with histopathological evidence of microthrombi in several organs, particularly in the brain, liver, lung, kidney and pancreas. A combination of mechanisms, including release of fat, phospholipids and thromboplastin from tissue—especially brain tissue—into the circulation, hemolysis and endothelial damage may promote systemic activation of coagulation. Cytokines also may have a role in the development of DIC.

The two recipients demonstrated a very slow increase in urine output postop associated with also small downtrending of the creatinine. A time zero biopsy showed multiple fibrin thrombi in the glomerular capillaries. As an important learning point, these allografts are usually associated with delayed graft function. Moreover, it is essential to ensure no significant necrosis is present on biopsy at time zero, before transplantation. It is believed that the recipient's own fibrinolytic system is able to slowly breakdown the thrombi and reestablish the renal function. Still, I was disappointed that the kidneys were last…

Hermansky-Pudlak Syndrome

This is one that Nate would have liked....I recently saw a case of renal disease in an albino Peurto Rican woman with severe pulmonary fibrosis. She holds the diagnosis of Hermansky-Pudlak Syndrome (HPS).
HPS is an autosomal recessive disorder characterized by

• Oculocutaneous albinism
• A bleeding diasthesis (absense of dense bodies)
• Sometimes pulmonary fibrosis
• Sometimes granulomatous colitis.
  

The prevalence is 1 in 500,000 in non-Puerto Ricans and 1 in 1800 in Peurto Ricans. The HPS1 gene is most associated with HPS in Peurto Ricans and for the pulmonary fibrosis which is usually fatal in 10 years from symptom onset.

The renal failure, pulmonary fibrosis, and granulomatous colitis are associated with lysosomal accumulation of amorphous lipid-protein complexes called ceroid lipofuscin. This is seen on the limited number who have undergone renal biopsy. The ceroid deposits accumulate in renal tubular epithelial cells of the proximal tubules with sparing of the glomerular epithelial cells and the distal tubular epithelium. Pathogenesis is still speculative and treatment options other than supportive care are currently unavailable.

Compensation for living organ donation! A taboo no more but....

Talking to Nate always stimulated new ideas and new challenges. Last time I met him, we played soccer in the park with the kids (that was also a challenge but fun and easy to win…). We also talked about an interesting hot ethical topic (It was hard and no winners…). Compensation for living organ donors! A taboo no more but nonetheless remains an ethical dilemma that needs public debate, engaging mainly specialists who care for end-stage kidney disease patients. I thought using Nate’s blog for such a debate will please him, so here we are…

My approach will be, what are the facts?

• We have an increasing demand for kidney transplantation that our deceased donor waiting list can’t match. And living donation is not increasing especially when being an organ donor can negatively affect the likelihood of obtaining life, disability and health insurance. This concern is frequently raised by many potential donors.
• Recipients of living donor kidney transplants do better than recipients of deceased donor transplants.
• More people are dying on dialysis waiting for a transplant.
• Kidney donation is safe (Ibrahim et al. NEJM 2009)… Trust me, I finally watched a hockey game last week after I saw a Canadian flag in our Lab.
• And for the government (no offense) and the health insurance payers, Matas et al found that a LURD transplant saved $94,579 (US dollars, 2002), and 3.5 quality-adjusted life years (QALYs) were gained.

So no doubt increasing living donation through creating incentives for donors will save lives and money. Also keep in mind that we pay blood donors, plasma and sperm donors, egg donors and surrogate mothers…

What are the ethical hurdles?

If we allow direct compensation between donors and recipients, we are turning the poor of our society into providers of body parts to wealthy people.
But what if the compensation is indirect through government agencies, providing donors, for example, with lifetime health insurance or tax deduction and maybe by treating them as the nation heroes which they deserve by the way.

I’ll be happy to hear your comments.

Familial renal glucosuria and a new drug for diabetes mellitus

The kidney contributes to glucose homeostasis by reabsorbing ~180 grams of glucose daily. Two sodium-coupled glucose transporters play an important role in this process, SGLT1 and SGLT2. Of these two, SGLT2 (encoded by the gene SLC5A2 on chromosome 16p11.2) is the transporter which is predominantly expressed in the luminal brush border of the proximal tubule (S1 segment) and mediates primarily renal glucose re-absorption.

Glucosuria, in the absence of diabetes mellitus, can occur in the setting of global dysfunction of the proximal tubule (PT), known as Renal Fanconi Syndrome. The latter is typically accompanied by excessive urinary excretion of amino acids, phosphate and bicarbonate. The occurrence of glucosuria in the absence of PT dysfunction and hyperglycemia is known as renal glucosuria or familial renal glucosuria (FRG) as it is recognized as an inherited disorder.

Patients with FRG have decreased renal tubular reabsorption of glucose from the urine in the absence of hyperglycemia or any other signs of tubular dysfunction. Glucosuria can range from 1 - 150 grams/1.73m2 per day. The majority of affected patients does not develop significant clinical problems and individuals are typically picked up during routine clinical tests. However, higher levels of glucosuria lead to osmotic diuresis and could cause volume contraction when access to fluid is limited.

Both, autosomal recessive and dominant pattern of inheritance for FRG have been reported. Mutations in SCL5A2 (encoding SGLT2) account for the majority if not all families with this condition. So far ~44 different mutations in 14 exons have been reported for FRG. Establishing a definite genotype-phenotype correlation has been difficult due to variable expressivity of SGLT2 and other genes that may have an overall impact on renal glucose reabsorption. In general, heterozygous mutations lead likely to mild glucosuria Here's a nice review.

In summary, FRG is a relatively benign condition nephrologists should be familiar with, especially with the availability of Dapagliflozin, a new drug for treatment of diabetes mellitus. First trials look promising since inhibiting SGLT2 appears effective and relatively safe.

Alimentary Azotemia?

I am currently a clinical fellow, slogging through another consult month. As I am sure many of you have experienced, consult questions often come in batches. At least three times this week we have been called to see a patient with markedly elevated BUN out of proportion to creatinine with the team questioning uremia, need for renal replacement etc. In all three cases, there had been an associated drop in hematocrit, and so we suggested they consider an occult gastrointestinal bleed as a contributor to the azotemia. Having suggested the association several times this week, I decided to investigate the azotemia-GI bleed association further.

The association was first noted by Sanguinetti in 1934, and he postulated that the observation was due to the absorption of protein from the digestion of blood, subsequently dubbed alimentary azotemia.

Several other theories about the cause of this phenomenon exist, including:

- hemorrhagic shock causing pre-renal failure

- increased protein catabolism as a result of negative nitrogen balance

- a toxic effect of some molecule absorbed that led to renal dysfunction

- direct effects of anemia.

Some authors have been dogmatic and insist that azotemia from GI bleed would only occur in the presence of renal dysfunction, acute or chronic.

This interesting study attempted to tease out the relative contribution of each of these factors (http://archinte.highwire.org/cgi/content/summary/75/6/381). Their model involved bleeding dogs and then feeding them back the blood while varying the degree of hypotension and access to and resuscitation with fluid. They found that dogs fed blood or dietary protein (meat) developed a small degree of azotemia over a short duration of less than 12 hours. On the other hand, dogs bled to the point of hypotension were azotemic to a greater degree and for a longer period of time. When dogs were bled to the point of being hypotensive and then fed back the blood, they were more azotemic and for longer than when hypotensive or fed blood alone. Moreover, after feeding dogs blood without making them hypotensive, they found urea clearance to be unchanged, arguing against a nephrotoxic effect of the ingested blood. Finally, varying water intake, in the absence of hypotension, did not affect the subjects' BUN. Other investigators conducted similar studies in humans, with the investigators or their colleagues serving as subjects.

It's hard to draw conclusions from these studies, but it certainly seems that both intestinal reabsorption and impairment in renal function may play a role in azotemia associated with GI bleed. Further, I think few would disagree that while the cause of azotemia after GI bleed is likely "multifactorial," the finding of a patient who is acutely (or even subacutely) azotemic out of proportion to Cr with associated anemia out of proportion to any underlying CKD, should prompt the consideration of a GI bleed.

I had the opportunity to talk to Nate on several occasions when he would moonlight and I would be burning the midnight oil on call. Our conversations would run the gamut from our families, to life as a fellow, to our passion for nephrology. Often I would mention one of his posts that I found particularly intriguing. On at least one such occasion, Nate asked whether I would be interested in contributing to the Blog in the future and I responded enthusiastically. Unfortunately, these are far from the circumstances under which I hoped to contribute. Nonetheless, I hope to do my best to perpetuate one of Nate's labors of love.

For my first post....

Creatinine: A Cautionary Tale

In recent months I've been seeing a number of referrals for patients with creatinine values in the normal range but eGFR as reported by the lab at below 60ml/min. This is particularly the case in middle aged women. Another group of cases troubling my Primary Care colleagues are male athletes with creatinine levels at or above the upper limit of normal but with no other apparent marker of kidney disease.

Certainly this is reflective of the weakness of using creatinine and creatinine based estimates of GFR as our basis for determining renal function. Unfortunately there are limited clinically applicable alternatives. What do we tell these patients? Do they or do they not have kidney disease?

My approach is the following:
1. Authenticate renal function within the office practice to the extent possible.
2. Check Cockcroft Gault creatinine clearance
3. Check 24 hour or 12 hour urine creatinine clearance
4. Rule out rising creatinine within normal range by reviewing historical data if available
5. Rule out Microalbuminuria or Proteinuria as markers of intrinsic renal disease
6. Rule out CKD risk factors (Hypertension, Diabetes, etc)
7. Consider a renal U/S to evaluate renal size.

If all these data are within normal limits then I reassure the patient and suggest a 6 to 12 month follow up and will repeat the studies to confirm a normal picture. If there remains doubt an Iothalamate measured GFR needs to be obtained. The issue of estimated versus measured GFR is reviewed by Andrew Levey and Lesley Stevens in an excellent article in JASN last year.

For those athletes with elevated creatinine levels I recommend the same process making sure they: discontinue all NSAID use; do not take any creatine based dietary supplements; and limit their meat intake to reasonable levels before performing the testing.

David Steele MD.

Revealed: my "covert" project with Nate a.k.a TRP channels in the kidney

Nate Hellman’s bench was three benches down from my lab. Nate and I trained together as clinical fellows. He and I had also brainstormed on research projects involving TRP channels and kidney disease. TRP channels are my research area of interest. It therefore seems appropriate to discuss some aspects of what Nate and I jokingly referred to as our “covert” project in my first blog posting.

What are TRP channels? And why do they matter in terms of kidney health and disease?

TRP stands for Transient Receptor Potential, a large family of non-selective cationic channels with diverse tissue distribution and diverse cellular functions. They were initially discovered in Drosophila (fruit fly) photoreceptors where they mediate fly vision. Some refer to them as “the last bastion of ion channels” since there is still much we do not understand about their role in health and disease. There are a few TRP subfamilies, indicated by letters which are there for various historical reasons (a discussion for another day – just take my word for it for now, or refer to a review by Ramsey et al., Annu Rev Physiol. 2006;68:619-47), but there are the TRPCs, the TRPVs, the TRPMs, the TRPPs, the TRPMLs and the TRPAs.

A few fun facts:
- TRP channels (TRPV1) are responsible for the hot taste of chili peppers in your mouth.
- TRP channels (TRPM8) also give you the cold sensation of menthol.

But how are TRP channels pertinent to your kidneys? It turns out that they are actually involved in many aspects of kidney physiology and disease (called “channelopathies”):

We’ll start from my favorite: Proteinuric kidney disease. Mutations in TRPC6 were found in a number of families with adult onset Focal Segmental Glomerulosclerosis. Many of us are now actively involved in research to identify the precise mechanisms by which disease occurs in these patients, but deleterious effects due to channel mutations in glomerular podocytes are strongly suspected.

Another channel, TRPV5, mediates vitamin D dependent calcium uptake in tubular epithelial cells. The absence of TRPV5 channels (at least in mice) causes renal calcium wasting and bone loss.

Perhaps more intriguingly, mutations in TRPM6 have been implicated in human hypomagnesemia with secondary hypocalcemia (HGH) as this channel is involved in renal magnesium uptake.

And rather famously, of course, polycystic kidney disease (ADPKD) emerges due to mutations in two slightly more distant relatives in the TRP family, the polycystins, known as TRPP1 and TRPP2.

This of course brings us full circle back to Nate and his research, which was focused on cystic disease, and specifically cystic kidney disease.

As this is my first time blogging, please let me know what you think, your comments and suggestions are welcome!

New contributors to the Renal Fellow Network

I'd like to welcome the following new contributors to the Renal Fellow Network, who will begin writing this week. Between them, they have a wide range of clinical expertise and research interests. I'm confident that their contributions will really enrich and improve the network.

Dr. Albert Lam, Research Fellow Massachussets General Hospital

Dr. Anna Greka, Attending, Massachussets General Hospital

Dr. David Steele, Attending, Massachussets General Hospital

Dr. Ernest Mandel, Clinical Fellow Brigham and Womens Hospital

Dr.Hakan Toka, Research Fellow Brigham and Womens Hospital

Dr. Jamil Azzi, Research Fellow Brigham and Womens Hospital

Dr. John Niles, Attending, Massachussets General Hospital

Dr. Julie Paik, Research Fellow Brigham and Womens Hospital

Dr. Leo Riella, Research Fellow Brigham and Womens Hospital

Dr. Lisa Cohen, Research Fellow Brigham and Womens Hospital

Dr. Mario Rubin, Attending, Massachussets General Hospital

Dr. Mary Lieu, Research Fellow Brigham and Womens Hospital

Dr. Matthew Sparks, Research Fellow Duke

Dr. Melissa Yeung, Research Fellow Brigham and Womens Hospital

If any readers of the blog have topics they would like covered, please get in touch. Also, please keep the comments coming; they're always appreciated!

A Man's Best Friend

I'm sure many of you have a pet dog. Well, as Rover quietly licks himself in the corner, few would believe that he may hold the key to unlocking the genetic secrets of human disease, as suggested by this fascinating article in this weeks Nature Genetics.

Dogs evolved from the wolf about 15,000 years ago and, as a result of plenty of random mating over that time period, developed a 'short-range' haplotype structure due to genetic recombination. This resulted in lots of genetic diversity, with a wide variety of genetic mutations occurring at a low frequency across the species.

People only began breeding pedigree dogs in the past 200 years or so, whereby animals with desirable physical or behavioral traits were paired. This was effectively an extreme genetic experiment, which concentrated a fraction of the population genetic variation within a single pedigree, resulting in the 400 or so unique breeds we know today. Unbeknown to dog breeders, as well as collecting favorable polymorphisms for physical traits, these dogs were also silently accumulating disease-causing genetic mutations of strong effect due to genetic 'hitch-hiking'. Pedigree dogs demonstrate exceptionally high prevalence rates of complex disease within breeds (sometimes ~ 15%!), including many kidney diseases such as polycystic kidneys, MPGN and nephrolithiasis.

Within each of these breeds, there are very high rates of linkage disequilibrium, as there hasn't been enough time for long stretches of DNA to be broken down by recombination. This makes genome-wide association (GWA) much easier than in human studies, such that for a simple Mendelian trait one may need as few as 40 dogs and a gene-chip with 15,000 SNPs (as opposed to thousands of patients and around a million SNPs in humans).

In the aforementioned study, the investigators examined the Nova Scotia Duck Tolling Retriever, a hunting dog with a very high prevalence of autoimmunity, including ANA positive lupus. Using a simple 2-step GWAS approach they identified no less than 5 novel candidate genes associated with the development of lupus, effectively blowing the field wide-open. Most of the genes identified code for proteins involved in the NFAT pathway of T-cell activation, including a calcineurin subunit. The existence of a disease-causing single nucleotide polymorphism in calcineurin suggests a possible genetic explanation for differential treatment responses to cyclosporin / tacro in Lupus. Furthermore, as the NFAT pathway is known to be involved in peripheral tolerance, these results may result in a ground-shift in our understanding of the mechanism of this disease.

Continuation of Renal Fellow Network

Thank you to everyone who has made contact with the Renal Fellow Network over the past week or so. Your outpouring of love and support has been a great comfort to Nate's family and friends at this difficult time.

Many have asked about the future of the RFN project. After discussion with Nate's family and mutual colleagues, it is my intention to continue the blog. There are a few logistical issues to resolve, but I hope to resume blogging soon. I am pleased to announce that I have received several generous offers of collaboration from Nephrology trainees and Nephrologists of different backgrounds and research interests. I am confident that we can maintain the high standard of content that Nate and the RFN are known for.

Nathan Hellman Rest In Peace

It is with great sadness and sorrow that I am writing to inform you of the passing of Nathan Hellman, MD, PhD, and founder of the Renal Fellow Network Blog. I worked with Nathan in the Division of Nephrology of the Department of Medicine, Massachusetts General Hospital (MGH), Boston, where we were both fellows. He passed away on February 13, 2010 at the Massachusetts General Hospital after a short illness.

Born in Houston, Texas, on December 8, 1973, Nathan grew up in Duluth, Minnesota. He attended Yale University, graduating magna cum laude. After Yale, he went to Washington University, where he obtained his MD/PhD. He did his residency training in Internal Medicine at University of Pennsylvania and became a member of the Division of Nephrology in 2007 as a clinical fellow in Nephrology. He was completing his fellowship as a research fellow and member of Iain Drummond’s research group. He was to be appointed a faculty member in July 2010.

Nathan was most importantly a wonderful husband, father, son and brother. At work, he touched all of our lives with his warm heart and spirit, great sense of humor and remarkable intellect. He was an exceptional scientist, a talented and insightful clinician and a remarkably kind and humble human being. He is survived by his wife, Claire, his two children, Sophie and Max, his parents, Dr. and Mrs. Hellman, his two sisters, and their families.

A Memorial Service will be held to celebrate his achievements and commemorate his contributions to the MGH community at the O’Keefe Auditorium on Wednesday, February 17th at 2pm, followed by a reception in the Thier Conference Room at 3.30pm.

In lieu of flowers, memorials can be sent to:

Nathan Hellman Memorial Fund
PO Box 471044
Brookline Village, MA 02447

Tamm-Horsfall Protein and Kidney Disease

Tamm-Horsfall protein (THP), or uromodulin, is a glycoprotein secreted by the renal epithelium, best known as the proteinacious framework of all urinary casts. It’s function in health is an enigma, but prevention of bacterial colonization of the urinary tract, inhibition of stone formation and the maintenance of water impermeability in the thick ascending limb of Henle are all possible. Mutations in the gene UMOD, which encodes uromodulin, cause familial juvenile hyperuricemic nephropathy, which Albert reviewed last month. Recently, a large GWAS from the CHARGE consortium identified SNPs within the UMOD gene as being associated with an increased risk of CKD, also reviewed by Nate.


In this months issue of JASN, Kottgen et al. provide a nice proof of principle of the GWAS approach, by demonstrating urinary uromodulin levels predict incident CKD, in a prospective, case-control study of ten years duration. These findings were then externally replicated. In addition, they identify a protective SNP which confers a reduced risk of CKD via reduced urinary urimodulin concentration. Although the biology remains to be determined, this finding further supports the role of uromodulin in the pathogenesis of common variant CKD.

Did you know your endothelium is hairy?

Just heard an interesting talk on endothelial dysfunction and its relation to nephrology.  One thing I learned is that the vascular endothelium is actually "hairy", as demonstrated from this electron micrograph (taken from this website). These little hairs are the endothelial glycocalyx, a gel-like layer of negatively charged proteoglycans and membrane glycoproteins which helps serve as a protective barrier from blood flow for the endothelial cells. You can't see it on standard light microscopy since it apparently requires special preservation techniques not normally used.  There is some data to suggest that vasculopaths and diabetics have a less developed and overall thinner endothelial glycocalyx compared to healthy controls, suggesting the importance of this structure in maintaining a healthy vasculature. 

In the kidney, the glomerular endothelium is a little different than most other endothelia in that they contain fenestrae:  actual pores in the endothelial cells which are large enough to let most proteins pass through, but small enough to exclude circulating blood cells. The glomerular fenestrated endothelium makes up a component of the glomerular filtration barrier (along with the glomerular basement membrane and the podocyte layers), and the classic teaching is that the negatively charged proteoglycans on this layer help form part of the charge barrier keeping albumin from getting filtered (though this is now being debated by some). Here are some pretty pictures of the glomerular fenestrated endothelium:

World Series of Poker Celebrity Kidney Transplant Recipient

Meet Jennifer Harman. She is apparently one of the most famous female professional poker players in the world, having done quite well at the prestigious "World Series of Poker" tournament. It turns out she is also a kidney transplant recipient, having undergone 2 transplants. Admirably, she has become a real advocate for patients with kidney disease, seeking to raise awareness for living organ donation. Recently, she announced that she would be donating 1% of all profits to the NephCure foundation, which funds research relevant to nephrotic syndrome and FSGS in particular.

Super Bowl Sunday Contrast Nephropathy Post

How common is contrast nephropathy in the general outpatient setting? When you send one of your outpatients to get a CT scan with iv contrast, what is the real risk?  Much of the randomized, controlled trial data on contrast nephropathy comes from INPATIENTS undergoing angiography or other procedures, often focusing on those with the greatest perceived risk of contrast nephropathy (e.g., diabetics, those with underlying CKD to begin with) in order to generate enough meaningful datapoints for analysis. An article by Mitchell et al in this month's CJASN reports the risk of contrast nephropathy in a mixed OUTPATIENT group--and finds that the risk of contrast nephropathy may actually be higher than what has generally been appreciated.

One big caveat, in my mind: even though the article is entitled, "Incidence of contrast-induced nephropathy after contrast-enhanced computed tomography in the outpatient setting," the phrase "outpatient setting" should be examined a little more closely. Their patient population wasn't exactly "outpatient" as we normally think of it; it was all the patients entering a large, academic emergency department who underwent CT scans with iv contrast. One could argue that by the very nature of their showing up in an emergency department (as opposed to their primary care physician office) they could be seen as "sicker" and therefore more susceptible to the effects of iv contrast use. Nonetheless, the researchers found that the incidence of contrast nephropathy (defined as an increase in serum creatinine greater than 0.5 mg/dL or greater than 25% of baseline between 2-7 days after contrast administration) was 11% (70 out of 633 patients receiving iv contrast), which is quite high. Not surprisingly, the development of CIN was also associated with an increased risk for developing severe renal failure and death.

There's still a lot of controversy about contrast nephropathy and just how significant it is--after all, the vast majority of patients see a return of their creatinine to baseline levels--but perhaps the knowledge that over 10% of patients in an emergency department show evidence of renal injury with a simple CT scan with iv contrast should make us think twice about ordering this test so frequently. 

Making Allograft Nephrectomies More Routine?

As much as kidney transplant outcomes have improved over the decades, we're not perfect: a sizable group of patients end up transitioning to dialysis therapies after the kidney transplant stops working. What should be done with the allograft once you've given up hope for any meaningful allograft function? In many transplant centers, the prevailing wisdom is simply to leave the allograft in place, as long as it is not causing any exceptional systemic inflammatory response as a result of prolonged rejection. If nothing else, it avoids an additional surgery in a dialysis population that is often plagued with comorbidities and the potential for surgical complications.

However, a recent study in this month's JASN by Ayus et al suggests otherwise, hinting that allograft nephrectomy might be considered as a more routine measure. The investigators probed the USRDS, looking at all transplant recipients who returned to long-term dialysis. A retrospective analysis demonstrated that those patients who had undergone an allograft nephrectomy had a 32% lower adjusted relative risk for all-cause death, even after controlling for factors such as age, comorbidities, and donor characteristics. The authors end the article by suggesting that "routine allograft nephrectomy in stable dialysis patients with a failed renal allograft should be evaluated against current management strategies in a randomized trial."

An accompanying editorial cautions against adopting this strategy too readily. They point out that patients in the allograft nephrectomy group tended to be younger and healthier, and even with appropriate adjustments to account for this, residual confounding and selection bias may well be altering the results. They also point to evidence that keeping the allograft in may actually be beneficial from an immune standpoint. Still, however, the retrospective by Ayus et al is intriguing and will doubtlessly be pursued further.

Warfarin and Vascular Calcification

Warfarin has recently been associated with an increased risk of stroke in ESRD patients with atrial fibrillation. This makes the decision whether to initiate warfarin therapy in dialysis patients with atrial fibrilltion anything but clear cut. Add to this the emerging evidence that it also promotes vascular calcification, and you have a real dilemma.

This latter side effect hinges on Matrix Gla protein, or MGP. In ESRD, vascular smooth muscle cells (VSMCs) undergo a phenotypic switch to take on the appearance of osteoblasts, in a well-described process thought to be driven by hyperphosphatemia. Once this has occurred, VSMCs lay down a protein matrix which can undergo calcification, similar to normal bone. MGP is an essential endogenous inhibitor of this process, mediated in part by it’s ability to bind calcium. This ability to bind calcium is a Vitamin K dependant process, explaining how warfarin may increase the risk of vascular calcification.

Warfarin has been linked to aortic valve calcification in both the general population and in ESRD, as well as calcific uremic arteriopathy in the latter. In fact, the odds ratio for severity of aortic valve calcification after 18 months of warfarin in ESRD was almost 4. Prospective trials are clearly needed, but for now, adopting a restrictive policy towards warfarin use in ESRD seems wise, such as reserving it for patients with a CHADS score > 2.

Drug Trials

Last week's poll results:  who should provide funding for large, randomized controlled drug trials?  Most respondents (58%) chose the diplomatic answer and said that it should be a combination between government and pharmaceutical companies.  I was somewhat surprised to note that more people felt that conducting RCTs should be the responsibility of the government (24%) rather than a responsibility of the pharmaceutical industry (only 7%), one of the most profitable industries within the U.S. currently. 

Check out the new poll question of the week in the right margin.

The trials of a lab rat...

I was on the phone to one of my friends the other day. He's a renal fellow currently doing lab-based research in Boston. He's been having a difficult time of it lately, with none of his experiments working out, and has understandably been getting a bit frustrated and disillusioned.

Me: "So, how's your research going? Any major breakthroughs?"

G: "Well, I've had an epiphany!"

Me: "An epiphany, that's fantastic! About time!"

G:"What do you mean fantastic, I said a rat pissed on me! I think I'm going to switch careers..."

Well, I thought it was funny...

The actin cytoskeleton of the podocyte

Peter Mundel, a well-known researcher of podocyte biology, gave our Renal Grand Rounds today.  Here's what I took away from this morning's talk:

-regulation of the podocyte's actin cytoskeleton is postulated to be the final common pathway in most instances of nephrotic syndrome/proteinuria.

-in some ways it is better to think of the podocyte as a modified smooth muscle cell rather than a modified epithelial cell based on its intricate network of actin & myosin which mediate contractility.

-the medication cyclosporine (used in the treatment of some refractory forms of nephrotic syndrome) acts NOT on modulation of immune cell function as previously assumed, but rather on direct effects on the podocyte actin cytoskeleton, as detailed in a prior post.

-a key event in generating abnormal, protein-leaking podocytes is turning them from a stationary cell to a motile one.  This key transition is mediated by three distinct Rho GTPase proteins, already established to mediate motility in several cell types. In general, Cdc42 and Rac1 promote podocyte motility, whereas RhoA promotes podocyte stabilization. It is possible that targeting these Rho GTPase pathways could lead to novel therapies for podocytopathies, and this is being investigated.  

Check out a good 2009 Kidney International review of the topic by Mundel and Reiser.

How Luminex Beads Work

You may have come across the phrase "Luminex beads" while doing your transplant nephrology rotation, or heard the term while hanging out in the Tissue Typing Lab. This post is intended to briefly describe the Luminex technology and how it works. A good review by Tait et al can be found here.  

Acute cellular rejection in kidney transplant recipients comes from the presence of recipient anti-HLA antibodies directed against donor antigens. How do we detect such antibodies and prevent donor-recipient mismatches from occurring? Traditionally--and still one of the most practical tests--we use the complement-dependent cytotoxicity (CDC) "cross-match" assay. While useful, however, more recent "solid-phase" technologies have allowed a more sensitive detection of anti-HLA antibodies in recipient serum, and the Luminex system is one of them.  

Briefly, the Luminex technology consists of a series of differently-colored polysterene beads, populations of which contain distinct HLA molecules attached to them. The lab incubates an aliquot of the kidney transplant recipient's serum with an aliquot of beads, and if there are any anti-HLA antibodies present they will bind to the beads. A second phycoerythrin-labelled anti-human IgG antibody (aka, a "secondary antibody") is then added, and after washing off unbound antibody, the beads are passed through a machine which works like a flow cytometer, dropping beads one-by-one through a narrow chamber. As the beads pass through the chamber, they are hit with lasers of a specific wavelength, exciting both the fluorescently-labeled secondary antibody AND the fluorochrome within the bead itself--thus allowing the detection and identification of specific recipient antibodies.  

There are different types of beads:  for example, some beads are coated with many different Class I or Class II molecules, designed to detect a wide range of recipient antibodies. Some beads are designed to be like a single cell, containing HLA antigens encoded by two different alleles from each of the Class I (HLA-A, B, & C) and Class II (HLA-DP, DQ, DR) loci. Finally, there are the "single antigen beads" (SAG), a bead coated with one sole antigen. This can be particularly useful in patients with a high PRA (panel reactive antibody)--you can actually identify the specific HLA antigens to which the individual is sensitized.  

While potentially quite useful, it is important to also realize the limitations of this technology. While much more sensitive than the standard CDC cross-match, it is not always clear what a positive antibody result means--though in most instances, the CDC cross-match is still the primary determinant as to whether a given kidney donor-recipient pairing is deemed acceptable.