Sunday, January 31, 2010

Green Peritoneal Dialysis Fluid

This month's Kidney International "Nephrology Image" features a report by Chen et al in which they describe a PD patient who noted cloudy, deep green dialysate fluid upon drainage of their peritoneum. They also presented with right upper quadrant pain and fever. Peritoneal white cell count was elevated with 84% neutrophils. The diagnosis? Gallstone peritonitis. The patient had a distended gall bladder with multiple pigmented stones; the greenish color is presumably from extravasated bile fluid. The authors make the case that "appearance of green color in the peritoneal dialysate should lead to immediate investigation of the biliary tract in patients with our without abdominal symptoms [as] asymptomatic perforation of the gall bladder has previously been reported."

Saturday, January 30, 2010

AJKD Bundling Editorials

This month's issue of AJKD includes an enlightening group of 6 editorials, each written from a unique perspective (e.g., the perspective of large dialysis corporations, the perspective of the ESRD Networks, the perspective of non-profit dialysis corporations, etc.), commenting on the proposed prospective payment system (PPS) for ESRD. The PPS is the so-called "bundling plan" which will radically change the way in which dialysis is reimbursed. For historical reasons, dialysis treatments are reimbursed based on 2 payments: (1) a flat-rate fee for the dialysis procedure itself (which dialysis units make very little, if any, profit on), and (2) "separately billable items", including injectable drugs such as Epogen, which in recent years have provided the majority of profit for dialysis units.

This will all likely change in the coming months as the PPS nears finalization. A single lump-sum payment will be charged which will taken into account not only the dialysis procedure but also all medications and laboratories provided during the dialysis procedure. Proponents of the PPS would argue that the ESRD Program already soaks up a large chunk of the Medicare budget (5.8% of the overall budget, despite affecting less than 1% of Medicare beneficiaries), and the "bundling" strategy will encourage nephrologists to use tests and medications (particuarly EPO) more judiciously, resulting in lesser overall costs.

However, there are several controversies with the PPS alluded to in many of these editorials. For instance: in the new plan, all labs ordered during dialysis would be included in the bunding plan. For instance, patients who need to have their INR monitored frequently can have their bloods drawn during dialysis, a practice which is probably both humane and having practical sense from a standpoint of preserving the vasculature for future fistula use. However, many are concerned that dialysis units will be resistant to provide this service for patients, as they will no longer be reimbursed for drawing these labs. Some point out that decreased lab work provided during dialysis will also have a negative effect on completing kidney transplant evaluations in a timely manner. Still others are concerned that many ESRD-specific oral medications (e.g., phosphate binders, cinacalcet) will also fall into the bundled payment: for nephrologists who are responsible not only for the health of their patients but also the health of their dialysis unit, might this not put nephrologists in the unenviable position of having to "ration" expensive oral drugs only to the patients deemed to deserve them the most? Finally, there is also concern that only the largest dialysis corporations will be able to compete with the new regulations, leading to the closure of several smaller and non-profit dialysis centers.

The final PPS is apparently still being tinkered with, so we don't know the exact details quite yet. However in reading these editorials it is clear that there remains some trepidation about how the bundling will change the dialysis landscape.

Friday, January 29, 2010

Rituximab in Refractory Lupus Nephritis

Linking up nicely with Nate’s rituximab post from this Tuesday, I wanted to mention a patient with lupus nephritis whom I saw in clinic this week. She had had horrendous renal disease, as seen on the three kidney biopsies she needed over the course of her illness. She failed to achieve remission despite multiple courses of steroids, cytoxan etc, but had the most remarkable response rituximab: complete remission after 2 doses, with a completely bland urinary sediment and a serum creatinine of 0.6 mg/dL one year out. I should also mention that she is now on maintenance MMF. Her case raises a few important questions; I used this review to try and answer some of them.

What’s the evidence for using Rituximab in refractory Lupus Nephritis?

To date, there is published data from over 20 studies, comprising 300 patients, of cases of refractory lupus or lupus nephritis treated with rituximab, with reported response rates of around 75%. However, positive reporting bias is a real concern, and no randomized trials in renal disease exist.

She continues to have very active serology; what does this mean?
Autoantibody levels in lupus and vasculitis do not predict relapse very well in general. The published studies report that responders will typically demonstrate a fall in anti–double-stranded DNA antibodies, and a correction of complement depletion. So, they appear to have more of a role in predicting response to treatment

She has had 2 doses of rituximab so far, without complication. Should she receive a third?
This patient has now been in remission for over 1 year. However, I’m concerned about the possibility of an impending relapse. Relapses are reported as occurring after an average of 10 to 13 months, although some patients maintain remission for several years. Also, her peripheral B cells (CD19+ or CD20+ lymphocytes) have recently recovered. Patients who fail to achieve depletion tend to have poor or no clinical response, whereas prolonged B cell depletion is associated with a prolonged clinical response. Protocol re-treatment at 4- or 6-mo intervals is under evaluation, so for now there is no good answer to this question.

Thursday, January 28, 2010

A Divided Consensus on Health Care Reform

Interestingly, there was a near 50-50 divide on last week's poll question regarding the surprising election of Republican Scott Brown to the U.S. Senate in the state of Massachusetts.  Many viewed the election as a referendum on public support of the health care reform movement, and if we are to believe this to be true then there are some significant public misgivings about the health care plan in its current form.  Amongst readers of Renal Fellow Network who responded to this poll, there were 45 votes who felt that Brown's election was a good thing and 43 votes who felt it was not--a roughly even divide.  Does that mean there is a roughly 50-50 divide of Republicans & Democrats amongst Nephrologists?  I'm not sure, but if so it would seem to parallel the current partisan divide within our country.
Check out the new poll question in the right margin which deals with funding of large randomized controlled trials of important drugs.

Wednesday, January 27, 2010

Glomerular Density and Predicting Progression in IgA Nephropathy

IgA nephropathy (IgAN) is an unpredictable beast, and identifying patients who will go on to develop progressive disease can be challenging. The classic predictors of progression, namely heavy proteinuria, CKD, glomerular sclerosis and tubulointerstitial fibrosis, are themselves just markers of advanced disease. There is a real need for better early histopathologic predictors of renal prognosis.

One promising prospect is glomerular density (GD), i.e. the number of nonsclerotic glomeruli per mm2, which was the focus of this recent study from Japan. The investigators performed a retrospective analysis of almost 100 IgAN cases with preserved renal function at the time of biopsy (average GFR 90 ml/min). Interestingly, they found that the GD varied hugely between patients, from 1 to 8 glomeruli per mm2. In multivariate analysis, only GD, and the presence of a cellular/fibrocellular crescent, were found to be significant predictors of progression. Patients with a low GD experienced more rapid decline in renal function, and this enhanced risk for progression was increased if a cellular/fibrocellular crescent was also present. Interestingly, the classic predictors of progression listed above did not predict prognosis, presumably due to the early stage of disease.

Of course, these findings will need to be replicated in other ethnic groups. Nonetheless, when a case of IgAN next appears at your biopsy conference, you should pipe up “what’s the GD?”. Just try not to look too smug when you do it.

Tuesday, January 26, 2010

Potential Use of Rituxan in Membranous Nephropathy

Take-home points from Mayo Clinic's Fernando Fervenza's excellent Renal Grand Rounds this morning, in which he addresses the potential use of rituximab as a treatment for membranous nephropathy:

-the "rule of thirds" that we learn about membranous nephropathy (e.g., 1/3 of patients will spontaneously remit, 1/3 of patients will stay the same, and 1/3 of patients will progress to ESRD) is not entirely accurate in that patients with an extremely high degree of proteinuria (e.g., more than 8-10 grams per day) have a very high rate of progression of kidney disease.  This becomes critical in interpreting the results of clinical trials; you really have to look at the baseline proteinuria characteristics of the cohort.

-in non-randomized controlled trials, investigators are finding that dosing Rituxan either using a 1gm iv at D+1 and D+15 protocol OR using a 375 mg/m2 every 4 weeks for 4 doses total leads to at least a partial remission in between 60-75% of membranous nephropathy patients, a rate which is seemingly greater than one would expect for spontaneous remissions. One such paper by Fervenza et al is shown here.  

-a randomized, controlled trial comparing Rituxan to another therapy (e.g., Cytoxan-prednisone or a calcineurin inhibitor) would really be necessary to fully recommend using this strategy in the treatment of membranous nephropathy.  However, it is not clear where the money for performing such a trial would or should come from--industry or government.  

-it may be necessary to look at longer end-points to fully assess the effectiveness of Rituxan.  Since Rituxan targets pre-B cells but not plasma cells, you presumably have to wait until the plasma cells die off for it to have full effect.  Furthermore, monitoring proteinuria (the current standard for evaluating clinical response) is not perfect since it may reflect chronic podocyte damage (which may take months to years to fully heal, if it ever does) rather than immunologically-mediated proteinuria.  

-it looks as if levels of the antibodies against the phospholipase A2 receptor which explains a good chunk of patients with membranous nephropathy correlates generally well with patients who respond to Rituxan; that is, patients who successfully achieve a remission with Rituxan tend to show a complete disappearance of this antibody as assessed by Western blog.  Although this does not prove causality, it does point to a potential means of monitoring patients for a potential response.  

Monday, January 25, 2010

The Business of Dialysis

An interesting figure in this month's ASN Kidney News details the quarterly earnings for three major dialysis companies in the U.S.: DaVita, Dialysis Corporation of America (DCA), and Fresenius.

Also included in the figure (not shown here) is the "revenue per treatment"--that is, how much profit each company obtains from the average patient's dialysis run. For example, Fresenius reported a revenue per treatment of $348 for the 3rd quarter of 2009. I'm not sure how they arrive at these numbers, but you can do a quick calculation to figure out how much a single patient dialyzing on the standard 3x/week schedule is worth to the company on a yearly basis: $348/treatment x 3 treatments/week x 52 weeks/year = $54,288.00/year. Like it or not, dialysis is also a business.

Saturday, January 23, 2010

ASN's New Logo

The American Society revealed its new logo with the new year: a male form with two glowing kidneys visible inside him, striding into the future (at least, that's my interpretation as to what he is doing--I guess alternate interpretations could include his being in the process of falling down, or perhaps hailing a cab...)

The logo replaces the traditional ASN logo, which is fairly simple:

You can learn more about the new ASN logo on the ASN homepage (just click on Mr. Kidney), but briefly the new logo is intended to go along with the ASN's new tagline, "Leading the Fight Against Kidney Disease," and is supposed to place greater emphasis on ASN's leading role in patient care and important kidney-relevant policies.

Friday, January 22, 2010

Interferon effects on the kidney

Interferons are cytokines which play a central role in the inflammatory response, and commercially prepared interferons have proven useful in the treatment of several diseases. For instance, interferon-alpha (often used in conjunction with ribavirin) is often used in the treatment of hepatitis C, and has also proven useful in the treatment of certain cancers, such as malignant melanoma. Interferon-beta has also been very successfully used in the treatment of multiple sclerosis. With the increasing use of interferons, however, has come the realization that they can have renal side effects in some patients.

A variety of mechanisms of injury have been reported, though most attention has focused on the ability of interferon therapy to cause proteinuria and nephrotic syndrome. This has been noted most commonly with interferon-alpha therapy, though in many of the patients with hepatitis B or C it may be difficult to be certain whether or not the development of nephrotic syndrome comes from the interferon therapy or a direct hepatitis-mediated renal injury such as MPGN. There have also been some recent case reports suggesting that interferon-beta can also cause a minimal change nephrotic syndrome in patients treated for multiple sclerosis and malignant melanoma.

Other mechanisms of renal injury reported with interferon use include acute tubular necrosis, acute interstitial nephritis, and even hemolytic-uremic syndrome. Occasionally, tubuloreticular structures as seen on electron microscopy of a kidney biopsy can be a clue as to the diagnosis of interferon-induced renal injury; these may also be seen in HIV-associated nephropathy.

Thursday, January 21, 2010

Gadolinium Beliefs

Poll results from last week:  The majority of individuals (60%) felt that it was definitely unsafe giving gadolinium to ESRD patients, with 45% of individuals also agreeing that it was unsafe in CKD stage 4.  As is consistent with the literature, most people did not feel that giving an individual with CKD Stage 3 gadolinium to be a problem.  The epidemiological data linking gadolinium to nephrogenic systemic fibrosis (NSF) (summarized nicely in this review by Dr. Derrick Todd of my home institution, Mass General Hospital) has been somewhat controversial given the frequency with which gado is administered and the relative rarity of NSF, but appears to be gaining acceptance.  Whether or not dialysis immediately after gadolinium exposure is effective in preventing NSF is still quite controversial, but my hospital has incorporated it into its policy to dialyze CKD4/5/ESRD patients exposed to gadolinium as the compound is removed by serial dialysis.  

Check out the new, politically-themed poll question of the week!

Wednesday, January 20, 2010

Bortezomib in Myeloma Cast Nephropathy

Bortezomib is a proteosome inhibitor used primarily in the treatment of relapsed myeloma. However, it is increasingly being used in the management of myeloma cast nephropathy (MCN).

Bortezomib binds to, and inhibits the function of, the 26S proteosome in plasma cells. This proteosome ordinarily performs a housekeeping function, degrading ubiquitinylated proteins, and hence clearing the cell of abnormal or misfolded proteins. Inhibition prevents degradation of pro-apoptotic factors and results in programmed cell death. The secretory nature of myeloma cells makes them particularly susceptible to agents which interfere with the ubiquitin pathway. Bortezomib has additional effects on other intracellular signaling systems, such as the NF Kappa B pathway, which may attenuate proximal tubular damage from nephrotoxic monoclonal light chains.

There are now several small case series suggesting bortezomib is efficacious in MCN. One of these reports on 20 patients with relapsed MM and creatinine > 2mg/dL. Renal failure was reversed in 40% in under 3 weeks. Additionally, 50% of patients had a 50% improvement in serum creatinine over the course of one month. Toxicity did not appear to be increased.

Bortezomib is given intravenously and does not require dose reduction in renal impairment. For these reasons, bortezomib is likely to have a particularly important role in the future management of patients with monoclonal Ig-mediated kidney disease.

(Image taken from NEJM June 26 2003 Volume 348; 2597-2598)

Tuesday, January 19, 2010

Cool New Cell Paper Demonstrates Molecular Basis for Thyroxic Hypokalemic Periodic Paralysis

The periodic paralysis syndromes are characterized by episodic attacks of acute muscle weakness, typically due to rapid fluxes in the serum potassium concentration, based on an abnormality in intracellular potassium shift. While there have been several instances of inherited mutations that cause periodic paralysis, there is also a subset of individuals who have thyrotoxic periodic paralysis (TPP), in which the presence of hyperthyroidism predisposes to attacks of transient paralysis. An article in this month's Cell by Ryan et al helps determine the molecular basis of TPP in many (but not all) cases, and characterizes this disorder as yet another example of a channelopathy: a disorder of ion channels.

Although thyrotoxicosis is a predisposing factor to this disease, there was also a clue that genetics was involved: Latin American and Asian populations appeared especially susceptible to TPP. The investigators identified a novel inward-rectifying potassium channel, Kir2.6 (interestingly, a gene which had escaped detection in all versions of the human genome thus far!), and sequenced this gene in affected individuals. In 33% of the unrelated patients in their sample, they identified mutations in Kir2.6 which appear to alter the function of this potassium channel and lead to an altered skeletal muscle excitability. Interestingly, the transcription of Kir2.6 was found to be altered by thyroid hormone, providing an explanation as to why the disease manifests itself most commonly during episodes of thyrotoxicosis.

Monday, January 18, 2010

The Undocumented ESRD Population

Although it is difficult to provide exact number, there are approximately 11 million illegal immigrants residing within the United States. Many of these individuals come from Mexico and other Latin American countries; since there appears to be a higher rate of kidney disease in Hispanics when compared to whites, it is not surprising that there exists a significant population of undocumented immigrants with ESRD. While the landmark 1972 Social Security Act provided dialysis for all those who need it, the law applies only to legal U.S. residents. What happens to undocumented ESRD patients in the U.S.?

Again, it is difficult to provide concrete statistics regarding a population which is essentially defined as being unmonitored, but it is clear that many individuals stay within the U.S. and somehow manage to obtain the life-sustaining dialysis treatments they need here. A recent AJKD paper by Hurley et al reported the results of a survey mailed out to ASN members, and 65% of respondants claimed that they had participated in the care of undocumented immigrants with ESRD, with 61% reporting an increasing prevalence of undocumented ESRD patients in recent years.
Who is paying for these dialysis treatments? As we all know, dialysis is expensive (I've heard $50,000 a year tossed around as a figure), and most undocumented immigrants simply do not have this type of income. Some do manage to obtain health insurance, and can pay for their treatments in this way. However, many don't, in which case it's often up to taxpayers (in some states, Medicaid will pay for dialysis treatments as an "emergency expense"), hospital systems, and dialysis organizations to pick up the tab. A well-publicized outpatient dialysis unit at Grady Hospital in Atlanta (see this excellent New York Times article) was losing approximately $3 million a year, in large part due to caring for a large number of undocumented ESRD patients whose treatments were not being reimbursed. The hospital seriously considered closing the unit, which would have left over 50 patients without access to the life-sustaining therapy they so desparately need, but ultimately decided to continue to operate the dialysis unit at a loss.

An article in this month's AJKD by Campbell et al summarizes the ethical dilemmas associated with care of the undocumented ESRD population quite nicely. The paper also states the current position of the Renal Physicians Association, which can be summarized as follows: all health care professionals have an ethical obligation to treat the sick (including ESRD), the federal government has an ethical responsibility to provide life-sustaining care for anybody within the U.S. borders, and because nephrologists are bound by physician-patient confidentialty agreements, they should not feel compelled to report illegal U.S. residents to the authorities.

This is a complex issue, and one which will doubtlessly need to be addressed in a more comprehensive manner in the future.

Friday, January 15, 2010

Pre-Op Cardiovascular Testing for Kidney Transplant Recipients

One of the challenges of taking care of your ESRD patients on the kidney transplant list is deciding on what kind of cardiovascular workup to perform. For obvious reasons, you don't want to be performing a major abdominal surgery on an individual with unstable coronary angina: cardiovascular disease is the most common cause of death with graft function at all times after transplant. Conversely, you also don't want to embark upon a costly, unnecessary, and potentially even harmful (e.g., contrast dye, possibility for atheroembolic disease) cardiac workup on a patient who doesn't have active cardiac issues.

The situation is even more confusing when you realize that patients with ESRD have an exceptionally high rate of coronary artery disease. This study by Ohtake et al performed screening cardiac caths on 30 patients with ESRD--and found that a full 53% of the sample had "angiographically significant CAD", including an even greater percentage (83%) in the subset of patients with ESRD and diabetes! Although it is controversial whether all of these patients would benefit from revascularization therapy, it makes the case that performing a "screening test" (such as ECHO or stress tests) is ESRD is not really worthwhile--you should just go ahead and cath everybody.

That being said, the more common approach to a cardiac workup in a patient being evaluated for kidney transplant is to use such a screening test. The two most popular are probably dobutamine stress echocardiography (which according to this recent AJKD review by Lentine et al has sensititives and specificities ranging from 37% - 95% and 71% - 95%, respectively) and myocardial perfusion studies (sensititives and specificities from 37% - 90% and 40% - 90%, respectively). As you can tell from the wide range of values reported above, the positive and negative predictive values of these tests are worse in the ESRD population than in the general population, making interpretation somewhat tricky. Electron beam CT scan, which determines a "calcium score" within coronary arteries to provide a risk assessment for CAD, has not been rigorously evaluated in the ESRD population.

The KDOQI Guidelines state that dialysis patients on the kidney transplant waiting list should undergo annual performance of non-invasive stress tests, such as those above, if they are considered "high risk"--which they define as having diabetes, known CAD, or having more than 2 traditional risk factors.

Thursday, January 14, 2010

Up To Date: The Nephrology Textbook of Today?

The Poll Results from last week were relatively convincing: Up To Date is the most commonly used current reference system for rapidly obtaining nephrology knowledge, with 67% of respondents declaring Up To Date as their top source. I certainly used this a lot as a fellow, though I also tend to use the primary literature (e.g., Pub Med or a familiar review) a lot as well. Googling is common (and according to this 2006 NEJM article by Steinbrook, more journal articles are accessed via Google than Pub Med--not sure if this is still true). Up To Date has historical roots in nephrology, as one of its cofounders, Dr. Burton Rose, is a nephrologist and electrolyte guru, author of one of the premier acid-base/electrolyte texts which should really be required reading for all nephrology fellow.

New poll starts tonight.

Wednesday, January 13, 2010

Polycystic Kidney Disease, mTOR and Sirolimus

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the gradual enlargement of multiple fluid filled cysts in both kidneys, which compress and destroy normal adjacent nephrons, typically resulting in ESRD by the fifth decade of life. Management has traditionally been limited to the treatment of the complications of hypertension and renal failure; however, several promising new therapies are on the horizon, such as nonpeptide vasopressin 2 receptor antagonists, inhibitors of the receptors for EGF and vascular endothelial growth factor (VEGF), and inhibitors of cmyc expression. All of which have been shown to inhibit disease progression in experimental models of PKD.

The mTOR inhibitor Sirolimus (Rapamycin) is another promising potential therapy, having also been shown to slow cyst development in rat models. Interestingly, it also slows the increase in size of native polycystic kidneys in human renal transplant recipients. It is currently the subject of three clinical trails underway in the US and Europe. Mechanistically, the cytoplasmic tail of wild-type Polycystin 1 normally interacts with, and inhibits, mTOR; loss of function of Polycystin 1, as seen in ADPKD, results in marked activation of mTOR within the epithelial cells of renal cysts. Sirolimus is believed to exert its effect via this mechanism. As mutations in PKD1, which encodes PC1, account for 85% of cases of ADPKD, Sirolimus has the potential to ameriorate the condition of the vast majority of APCKD patients.

Tuesday, January 12, 2010

Differential Diagnosis of Granulomatous Kidney Disease

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

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

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

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

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

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

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

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

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

7. Idiopathic.

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

Monday, January 11, 2010

Carotid Endarterectomy for CKD Patients

Cardiovascular complications are the major cause of morbidity and mortality in patients with CKD and ESRD. Although myocardial infarction and sudden cardiac death get a lot of attention, stroke is also extremely important in this population. How should carotid stenosis (a major risk factor for stroke) be handled in patients with CKD and ESRD?

In patients without CKD or ESRD, either carotid endarterectomy or carotid stenting are commonly used strategies; however, many surgeons are reluctant to advise such procedures in patients with kidney problems. For one, definitive diagnosis often relies on imaging that involves injection of either iv contrast dye or gadolinium, which have well-documented complications in patients with CKD. Furthermore, patients with CKD/ESRD are more likely to suffer surgical complications than those without.

Interestingly, however, a new paper in this month's JASN by Mathew et al (with an accompanying editorial) describes a subgroup analysis of CKD patients within the North American Symptomatic Carotid Endarterectomy Trial (NASCET), a large randomized trial of carotid endarterectomy versus medical management in which creatinine levels were routinely available. They found that individuals with a GFR less than 30 ml/min and symptomatic high-grade carotid stenosis (defined as greater than or equal to 70% stenosis) who do NOT undergo carotid stenosis have exceedingly poor outcomes. Although the study requires the usual caveats associated with subgroup analysis such as the presence of unforeseen confounders, these data will likely provide a stimulus to consider carotid endarterectomy more routinely in individuals with kidney disease.

Sunday, January 10, 2010

Hydrothorax in periteonal dialysis patients

In patients undergoing peritoneal dialysis, hydrothorax is defined as the presence of peritoneal dialysate fluid in the pleural cavity. This PD complication has an incidence of <5%>high glucose concentration and a variable cell count.

Patients diagnosed with a hydrothorax should be advised to temporarily cease PD. If necessary, patients can be transiently converted to hemodialysis while waiting for resolution of the hydrothorax. A trial of re-introducing low pressure PD (e.g. small volume) can then be attempted. If this strategy fails, switching to hemodialysis is a viable option. Video-assisted talc pleurodesis or operative repair are other alternatives available to patients who wish to continue PD.

Saturday, January 9, 2010

Hypercalcemia of Malignancy

Cancer-associated hypercalcemia is the #1 cause for hypercalcemia in the inpatient setting (in the outpatient setting, the main cause is primary hyperparathyroidism). In general, hypercalcemia of malignancy portends a poor prognosis, and there are three main mechanisms by which hypercalcemia can occur:

1. PTHrP (PTH-related peptide): this is the most common cause of hypercalcemia of malignancy, and is sometimes referred to as "humoral hypercalcemia of malignancy." The PTHrP essentially mimics the effects of PTH by virtue of its interaction with the PTH receptor, though since PTHrP is not detected by standard PTH assays the measured PTH level is typically very low. Sending a PTHrP level may be helpful, though in my experience it often takes several days to come back. PTHrP is most commonly secreted by solid tumors, such as breast cancer.

2. osteolytic metastases: this is the 2nd most common mechanism of hypercalcemia of malignancy, and is due to osteoclast-mediated bone breakdown. It occurs in characteristic tumor types, which can be recalled by this nifty mnemonic, "BLT with a Kosher Pickle, Mustard & Mayo":
B = breast cancer
L = lymphoma, lung cancer
T = thyroid cancer
K = kidney cancer
P = prostate cancer
M & M = multiple myeloma

3. tumor production of calcitrol: the mechanism is here is similar to that of granulomatous disease: tumor cells provide enzymatic synthesis of 1,25 OH-vitamin D, the active form of vitamin D, leading to unregulated GI uptake of calcium. It is most commonly seen in Hodgkin's lymphoma and some cases of NHL as well. It can be diagnosed by finding an elevated 1,25 OH vitamin D level in the presence of malignancy.

Very, very rarely one can observe ectopic PTH secretion as a mechanism for hypercalcemia of malignancy.

Thursday, January 7, 2010

Favorite Renal Consult Topics

Poll results: the most appealing Nephrology Consult scenario chosen, perhaps not surprisingly, was workup of new-onset glomerulonephritis (44%). I would contend that many individuals choose Nephrology because they are interested in issues such as glomerulonephritis, interesting electrolyte and acid-base cases, and workup of new-onset renal failure--even though the bulk of the work is dialysis and access-related.

Check out the new poll question in the right margin.

Wednesday, January 6, 2010

SGK1, Hypertension and the Metabolic Syndrome

I was recently asked the mechanism by which insulin resistance causes sodium retention and hypertension, and had to lie. Here's what I should have said.

Serum and glucocorticoid-inducible kinase 1 (SGK1) is an enzymatic central orchestrator of many renal processes and electrolyte balance, and is the likely cause of sodium retention and hypertension in insulin resistance states such as the metabolic syndrome. SGK1 transcription is stimulated by a wide variety of factors, most notably insulin, glucocorticoids, activated Vit D, PPAR gamma agonists and ischemia. Teleologically, the SGK1 system probably developed to permit the excretion of the large amounts of potassium, and conservation of the relatively low amounts of sodium, present in the diets of the Paleolithic era. To acheive this, activation results in the stimulation of the following cellular processes:

- Stimulation of renal ion channels, incl. ENaC, ROMK, TRPV5, N/K ATPase and voltage-gated K channels
- Regulation of mineralocorticoid stimulation of salt appetite
- Glucocorticoid stimulation of the Na+/H+ exchanger and nutrient transport
- Insulin-dependant salt sensitivity of blood pressure
- Salt -sensitivity of peripheral glucose uptake

Interestingly, an SGK1 gene variant present in 3-5% of Caucasians and 10% of African Americans is associated with obesity, hypertension and the development of diabetes. Here's a short review from a recent NephSAP editorial (beginning on page 61), from which the adjacent diagram was also taken.

Tuesday, January 5, 2010

Differential Diagnosis of Hypomagnesemia

Why do we care about hypomagnesemia? And why are cardiologists so eager to replete the serum magnesium above 2.0 mg/dL?

Very low serum Mg can result in serious cardiovascular and CNS effects. Specifically, hypomagnesemia can cause QRS widening and may predispose to various arrhythmias (there is a nice section on this in Up-To-Date under "Significance of Hypomagnesemia in Cardiovascular Disease." Furthermore, very low serum Mg can result in CNS effects such as coma or seizure. In addition, hypomagnesemia is linked with two other important electrolyte abnormalities: hypokalemia (reflecting the clinical pearl that it is nearly impossible to correct total body potassium stores while the serum magnesium remains low) and hypocalcemia (which can result from hypomagnesemia-induced PTH resistance).

The following is one potential approach to hypomagnesemia:

1. Decreased Magnesium Intake: The big one here is chronic alcoholism, which is actually thought to be related both to a nutrititonal deficiency of Mg as well as a renal Mg wasting effect of EtOH.

2. Redistribution of Mg from the Extracellular to the Intracellular Space: This can occur as part of the constellation of electrolyte abnormalities seen with refeeding syndrome, hungry bone syndrome, or during the treatment of DKA.

3. GI Losses of Mg: This can result from nearly any cause of chronic diarrhea (e.g., Crohn’s Disease, hx small bowel resection, chronic infectious diarrheas, etc), as well as losses from vomiting or NG suction.

4. Renal Losses of Mg: Perhaps the most common cause of renal Mg wasting is simply diuretic use: both thiazide and loops diuretics can cause renal Mg loss. Other drugs (e.g., amphotericin B, aminoglycosides, cisplatin, pentamidine, cyclosporine, and tacrolimus) are also common culprits. Hypercalcemia also inhibits renal magnesium uptake. There are also a variety of genetic diseases that result in renal Mg loss, including Gitelman Syndrome, Bartter Syndrome, mutations in the paracellin or TRPM6 genes, and many others.

Monday, January 4, 2010

Familial juvenile hyperuricemic nephropathy

I recently saw my first patient formally diagnosed with familial juvenile hyperuricemic nephropathy (FJHN), and since I had little prior knowledge about this condition, I decided to read up. Apparently, FJHN is more common than we think, and questions relating to FJHN do show up on renal boards.

Originally described by Duncan and Dixon in 1960, FJHN is an autosomal dominant disease characterized by
hyperuricemia, gout, and progressive renal failure. It was only recently discovered that FJHN was caused by mutations in the UMOD gene encoding the protein uromodulin, an 85 kDa glycoprotein involved in renal stone formation, the modulation of immune responses, and urothelial cytoprotection. These mutations lead to reduced renal excretion of urate. In vitro animal models of the disease suggest that the mutant forms of uromodulin cause the protein to be retained in endoplasmic reticulum, which inhibits normal trafficking to and expression at the cell surface. Patients often present in early adulthood with hyperuricemia or gout and normal blood pressure. The fractional excretion of urate is generally low. Renal dysfunction in these patients develops between ages 15-40 and is progressive, usually leading to ESRD in 10-20 years. On biopsy, patients are found to have chronic interstitial nephritis as well as thickening and splitting of the tubular basement membrane.

The optimal treatment strategy for FJHN is not clear at this time. Treatment with allopurinol to prevent gout has been recommended, though it remains uncertain as to whether or not allopurinol offers any significant benefit to preventing progression of renal disease.

Saturday, January 2, 2010

Basics of PD prescription writing

Concerning the basics of PD prescription writing--and only the basics, since there's lots to say about this interesting topic--the minimum prescription should specify the following:

1. What kind of PD does the patient use: for the most part, we distinguish between CAPD (continuous ambulatory peritoneal dialysis, in which the individual manually performs fluid exchanges, often several times throughout the course of a day) versus CCPD (continuous cycling peritoneal dialysis, in which a PD "cycler" machine is used to perform automated exchanges, usually at night), though often components of both are part of the prescription.

2. How much fluid volume per bag? Usually either 2 Liter or 2.5 Liter bags are used.

3. What percentage of dextrose solution is used? I've included in a previous post the common color-coding scheme PD patients use to specify which solution they use; this is often invaluable because patients often know only what color bag they use, not the numerical value of how much dextrose is in their PD fluid. The higher the % of dextrose, the greater the amount of UF is generally achieved.

4. How many exchanges per day? For CAPD, this may be as simple as saying that a patient gets 4 exchanges a day. However, the answer may be more complicated for patients who use a cycler.

For example: a typical CAPD script might look like this: 2 Liters x 2.5% x 4 exchanges per day.

Another common dilemma encountered by renal fellows is what to do with CCPD patients who are admitted to the hospital, since cyclers are rarely available for inpatient use and patients do not always bring their own into the hospital. Generally, cycler regimens can be converted to CAPD regimens by calculating their total daily infusion volume and then dividing this by 4 exchanges per day.

Other details of the PD prescription worth mentioning: often one needs to distinguish between "low calcium" and "regular calcium" dialysates; some patients will regularly use heparin with each fill; and icodextrin is being increasingly used for individuals who fall into the "high transporter" category of PD patients.

Any questions? Your best bet is usually just to call the PD nurse on call--in my experience, they tend to know their individual patients extremely well, and can troubleshoot most technical issues relatively rapidly.

Friday, January 1, 2010

History of Cystoscopy

I stumbled across a bit of Nephrology/Urology history the other day while strolling around a hospital in Paris: this plaque commemorating one of the key steps in the invention of ureteroscopy and cystoscopy. The plaque can be found at Hopital Necker-Enfants Malades, a large hospital now especially renowned for the treatment of pediatric illnesses (and also happens to be the birthplace of the stethoscope by Laennec in 1816).

A free article on the Development of the Modern Cystoscope via Medscape can be found here. The French instrument described above was not the first attempt at endoscopy, but was apparently one of the earliest. It is described as a "long metal channel through which a mirror reflected light from a petroleum-fueled lamp," and could be used to demonstrate the presence of gallstones and kidney stones in some situations. However, one of its major limitations was that the metal heated up pretty quickly and caused significant patient discomfort. I can't imagine being one of the first patient subjects trying out the new, experimental cystoscope...