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.

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.

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.

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.

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.

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.

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.

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.

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.

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...

New Year's Eve Poll Results

Happy New Year's Eve! I found the results of last week's poll to be surprising...well, I guess I shouldn't be too shocked to see that Nephrology Fellows won the "hardest working fellow in show business" award, being that this is a nephrology-related blog and individuals have a tendency to view themselves as being excessively overworked. Rather, I was shocked by the paltry showing of Gastroenterology Fellows, who in my opinion have a rather tough job at the three major hospitals I've done post-graduate training at (Penn, Brigham, & Mass General). It just seems like there is an endless supply of GI bleeders, and it's not uncommon that they'll get called in during the middle of the night to do a procedure. While Nephrology fellows get called in for dialysis, for the most part the labor involved should be relatively predictable (evaluate patient for need for dialysis, consent, place line, begin dialysis) compared to doing emergent procedures. In any case: most fellows work pretty hard, and my guess is that there is probably a greater variability amongst fellows within a given subspecialty than there are comparing different subspecialty groups with one another. Happy 2010 to fellows from ALL walks of life.

New poll question to jump-start 2010.

Complications of EPO Use

Well, I had hoped to be more of an active blogger during my holiday vacation this year, but my internet access has been much spottier than desired way out in the boondocks of Western France (not that I expect any renal fellows stuck in the hospital to be sympathetic to my plight in the slightest...) I'll post when I can:

Here's a list of some complications of erythropoietin use:

1. Increased thrombotic events. As the CHOIR study and others have now convincingly shown, elevated hemoglobin targets in CKD/ESRD patients are associated with an increased risk of cardiovascular events (the CHOIR study in particular demonstrated a hazard ratio of 1.34 in CKD patients randomized to a high Hgb target compared to a lower Hgb target, using a composite endpoint of death, MI, CHF requiring hospitalization, and stroke).

2. Hypertension: Patients may even experience intradialytic hypertension after receiving erythropoietin.

3. AV graft thrombosis: again, this correlates with the first point, that elevated Hgb concentrations can result in increased thrombotic events.

4. Pure red cell aplasia: rarely, patients can develop anti-EPO antibodies that result in pure red cell aplasia; this was predominantly associated with a form of EPO (Eprex) not marketed within the U.S.

5. Seizures: via a mechanism that appears uncertain.

6. Progression of diabetic proliferative retinopathy: because EPO has some angiogenic activity, it has been suggested to cause worsening of diabetic retinopathy, with some clinical studies appearing to confirm this hypothesis.

A second look at dilantin

The first time phenytoin was addressed as a blog on this site was on the one year anniversary of the inauguration of the RFN. I'd just like to bring it up again, because a question pertaining to phenytoin and its effect on serum calcium levels recently showed up on the nephrology boards. The aim of the question was to highlight the association between phenytoin and hypocalcemia. Interestingly, phenytoin and a number of other anti-epileptic drugs have been implicated as causes of hypocalcemia as well as other disorders of bone mineral metabolism (for a brief review, refer to Pack et al Cleveland Clinic Journal of Medicine 2004; 71:S2). There are a number of proposed hypotheses to explain the association. To begin with, phenytoin induces the cytochrome P450 system, leading to the catabolism of 25-dihydroxyvitamin D and reducing bioavailable vitamin D levels. Consequently, this can indirectly reduce calcium absorption from the gut and cause hypocalcemia. Phenytoin itself has been shown to directly impair the absorption of intestinal calcium in rats. In fetal rats, phenytoin can also impair the cellular response to PTH; the impaired responsiveness of bone to PTH could result in hypocalcemia. While these proposed mechanisms have mainly been observed in animal models, one should still be aware that there is a link between phenytoin and bone disease and that hypocalcemia is relatively frequently seen in patients chronically taking phenytoin.

Mount Rushmore of Nephrology Announced

The readers have spoken and it is time to announce the results of the hypothetical "Mount Rushmore of Nephrology":  the four Nephrology Pioneers whose contributions have mattered most, and deserve to have their imagery preserved forever on a big slab of rock.  The four highest vote-getters over the week were:

1.  Willem Kolff (inventor of dialysis)

2.  Belding Scribner (access pioneer, founder of 1st outpatient HD unit)

3.  Homer Smith (pioneer of renal physiology)

4.  Joseph Murray (Nobel-winning surgeon who performed 1st kidney transplant)

A few comments on these choices.  First, the top two leading vote-getters were both dialysis-related--which is indicative of the dominant role that dialysis has played in the evolution of nephrology, a field which was early on founded more on issues such as electrolyte abnormalities and medical diagnosis using the urine sediment rather than renal replacement therapy.  Second, I debated as to whether or not to put Joseph Murray on the list--he is, after all, a surgeon rather than a true nephrologist, and to some degree I was hoping that John Merrill would have been the representative for the field of transplant nephrology instead.  Then again, Homer Smith ("Father of Renal Physiology") also may not be considered by some to be a "true nephrologist" since he was not an M.D.--he was really a basic scientist/physiologist. Who knows, perhaps in another 50 years, the list might look different.

Check out the latest poll question on the right.  For those renal fellows working on Christmas Eve/Christmas Day:  may your pager be silent for as long as possible!  

Angiojet as a Cause of AKI??

The Angiojet Rheolytic Thrombectomy System is a medical device currently used to re-establish blood flow in a variety of settings. Briefly, a catheter is introduced into an area of thrombosis and a saline stream is directed towards the thrombus of interest. These saline jets generate a localized low pressure zone via the Bernoulli principle, leading to breaking up of the thrombus. The saline and clot particles are then sucked back into the catheter, avoiding potential embolic complications.

Angiojet has been primarily used for removing thrombus from arteries--for example, in acute myocardial infarction or acute graft thrombosis, for instance. It's also been useful in restoring flow in some dialysis accesses. More recently, however, efforts to use Angiojet in the treatment of venous clots--such as DVT or pulmonary emboli--have been attempted.

At a recent Renal Grand Rounds, one of the fellows presented an interesting case of a patient who developed acute renal failure shortly after undergoing attempted Angiojet therapy for a pulmonary embolus. In addition to a rising creatinine and oliguria, the patient developed red, heme-positive urine with only a few red blood cells, and labs reflecting intravascular hemolysis. Although it is not yet rigorously defined as a cause of acute renal failure, others have reported an association between Angiojet and AKI. It is possible that the Angiojet procedure is more likely to result in hemolysis if thrombectomy is attempted in a large, open space (e.g., for treatment of DVT/PE in a larger vein), as there have generally not been such complications when Angiojet has been used in restoring flow to arteries where the area of thrombus is relatively localized.

It will be interesting to see if there are further reports of this type of AKI with Angiojet.  I purposely put TWO questions marks in the title since I fully admit that much more work needs to be done in order to actually prove causality.  

Differential Diagnosis of Red Urine

Red urine: it's not always hematuria. The first step in evaluating the patient who complains of grossly red urine is to perform a standard urinalysis, focusing on (a) whether or not the dipstick turns heme-positive, and (b) whether or not there are red blood cells visualized on microscopic examination.

We are all fairly familiar with the basic differential diagnosis for heme-positive urine with RBCs visualized on microsopic exam: the presence of dysmorphic RBCs and casts is consistent with glomerular hematuria (e.g., glomerulonephritis) while non-dysmorphic RBCs warrants a work-up for lower-tract hematuria (e.g., nephrolithiasis, bladder cancer, etc.).

However, a heme-positive urine specimen in which RBCs are NOT seen on microscopic exam suggests the possibility of either myoglobinuria (e.g., rhabdomyolysis) or hemoglobinuria (e.g., hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc). A simple way to differentiate between these two possibilities is to centrifuge the patient's blood: the serum fraction will be pink in hemoglobinuria, and clear in myoglobinuria. Myoglobin is a 17kD protein which is rapidly filtered and excreted by the kidney; thus, it should generally not be present in high abundance in the serum. In contrast, hemoglobin exists as a tetramer of 69kD which is bound to haptoglobin, thereby restricting its filtration at the glomerulus and causing the serum fraction to be pink-tinged. Other lab values (elevated CK in the tens of thousands in rhabdo; positive Coomb's test and low haptoglobin in hemolytic anemias) can also be instrumental.

The differential for heme-negative red urine includes some more esoteric diagnoses: acute porphyria, ingestion of beets or certain food colorants, drugs (e.g., rifampin, pyridium, doxorubicin).

Cardiovascular Complications of Kidney Disease

Question: Who is the most important medical subspecialist for a patient with CKD to have regular contact with? Is it the nephrologist? A case could be made, relying purely on mortality statistics, that it's actually the cardiologist. CKD/ESRD leads to a wide range of cardiovascular complications. A quick review:

1. Hypertension: it is rare to find the ESRD patient WITHOUT hypertension. Along with a high rate of essential hypertension afflicted the general Western population, ESRD patients are at the additional disadvantage of having to deal with hypervolemia and sodium retention, which can made BP very difficult to control. Common ESRD medications such as EPO is also associated with high blood pressure, as is secondary hyperparathyroidism.

2. CHF: Both systolic and diastolic dysfunction are commonly associated with CKD/ESRD; in particular, there is a very high rate of LVH (both concentric and eccentric LVH). Furthermore, patients with AV fistulas or severe anemia can develop high output CHF.

3. CAD: CAD is exceptionally high in the CKD/ESRD population, though the mechanism of cardiac ischemia is posited by some to be discretely different from the standard "rupture of an atherosclerotic plaque" model which has been studied primarily in non-CKD/ESRD populations. Although serum troponin levels may be slightly elevated in CKD/ESRD patients simply because it is cleared less efficiently, even small elevations of cardiac troponins in these patients are associated with poor outcomes. Many hypotheses have been put forth regarding the increased CV risk associated with dialysis; the currently favored ones include abnormal calcium-phosphate metabolism, chronic inflammatory state, dyslipidemias, the accumulation of hypothetical cardio-toxic uremic toxins, and the high rate of association between CKD and diabetes.

4. Arrhythmias/Sudden Cardiac Death: The dialysis unit is a great place to uncover underlying EP abnormalities: there are non-physiologic fluid shifts, rapid changes in electrolyte concentrations, and the patient is being closely monitored.

5. Pericardial Effusions: Both uremia and dialysis itself can be associated with pericardial effusion. Main intervention: intensify dialysis.

6. Valvular Abnormalities: in particular, valvular calcifications can result from abnormal calcium/phosphate metabolism. These patients tend to do poorly with valvuloplasty procedures.

7. Pulmonary Hypertension: it is important to be aware of pulmonary hypertension in the patient with CKD/ESRD as it may make the patient ineligible for renal transplantation if it is too severe.

Ischemia-Reperfusion Models

The study of AKI/ATN has relied heavily on one particular animal model: the warm ischemia-reflow model (often referred to as "ischemia-reperfusion injury"), in which one of the renal arteries is transiently ligated off for a set period of time while body temperature is maintained, then opened up and allowed to reperfuse the kidney. A recent review in Kidney International by Heyman et al addresses some of the limitations of this model, mostly in terms of differences between the mouse model of ischemia-reperfusion and the typical human AKI/ATN we experience clinically.

Some the important differences between mouse and human AKI: First, while the warm ischemia-reperfusion model tends to initially target the S3 segment of the proximal tubule and typically leads to overt tubular necrosis, in human AKI necrosis is not always present, and when it is tends to be patchy and most commonly affecting the distal nephron (in particular: the medullary thick ascending limb and medullary collecting ducts). Second, in clinical practice it is COLD ischemia which is often the mechanism of injury (e.g., surgical procedures in which the aorta is cross-clamped is often performed in the setting of a lowered core temperature, and donated kidneys are typically stored on ice prior to transplantation), rather than warm ischemia. Overall, the authors conceded that the rodent ischemia-reperfusion model has been invaluable, but caution against using it to explain all aspects of human AKI/ATN.

The notion of whether AKI/ATN occurs primarily in the proximal versus the distal tubule is not merely of academic interest. According to one version of the "distal nephron model", the reduced GFR experienced in response to medullary hypoxia is actually an adaptive response: decreasing the metabolic demands of tubular epithelia would decrease hypoxic injury; in a sense one could think of the nephrons as "hibernating" in a low metabolic state until they sense that the hypoxic insult has been removed and they can resume optimal cellular function. If this is true, it might caution physicians from trying to stimulate GFR in patients with AKI, instead encouraging attempts to limit tubular energy expenditure.

IgA Nephropathy Treatment Poll Results

The results of last week's poll on IgA Nephropathy are in:  90% of individuals correctly identified that the only treatment shown in randomized controlled trials to consistently benefit patients with IgA Nephropathy is ACE-inhibitors and/or ARBs.  The response was pretty divided beyond that, however, with a variable number of individuals (37% in all) opting for a trial of immunosuppression.   In retrospect, I'll admit that the question was not perfectly worded: whether the patient has already been treated with ACE-I/ARB therapy was not really clear.  If the patient is just recently diagnosed with IgA Nephropathy, a case could be made to avoid immunosuppression initially and to see whether or not ACE-I/ARB therapy alone could suppress proteinuria and hypertension to acceptable levels.  According to this review in Brigham & Women's "Nephrology Rounds" from 2007, a trial of steroids or possibly even more aggressive cytotoxic therapy (e.g., cyclophosphamide) could be attempted in an individual with these lab parameters who is not responding to conservative therapy.  A majority of folks said they would use fish oil, a topic which has been covered previously.  

This week's RFN Poll question is a fun one:  let's assume Obama's stimulus package includes in its budget funding for a "Mount Rushmore of Nephrology" to be built.  This gigantic statue will feature the faces of 4 prominent nephrologists etched into the rock face of a majestic mountain, preferably at one of the national parks in the Western United States. Of all the prominent nephrologists, which four would you choose as being the most influential in the field?  Choose from the list of historic figures listed, and feel free to include "write-in votes" under the "comments" section if your favorite nephrologist is not listed.  The list I made is admittedly biased towards physicians who have been practicing recently enough that the subspecialty has actually been in existence (e.g., not including folks like Hippocrates), and conversely I tended not to include the current heavy hitters of Nephrology, reasoning that the jury is still out on these folks.  Realize that this is for fun, and I'm sure I've made several oversights.  

Transplant Glomerulopathy

As acute rejection rates continue to fall, causes of late allograft loss, such as transplant glomerulopathy (TG), become increasingly important. TG should spring to mind when you encounter a renal transplant recipient who develops heavy proteinuria and progressive allograft failure, usually late post-transplant. The clinical presentation overlaps with that of chronic allograft nephropathy, although proteinuria tends to be greater in TG and patients are likely to have a history of donor-specific anti-HLA antibodies. The pathogenesis is believed to relate to the presence of these donor-specific antibodies, which are often often anti-HLA Class II. These may wax and wane in concentration and, as a result, may not be detected on a single assay but repeat testing is usually successful. C4d staining is typically negative.

Various immunosupressive regimens have been tried, but none are known to be effective. Progressive graft failure and return to dialysis is the usual outcome. Finally, the increasing use of protocol biopsy informs us that ultrastructural changes that predate the TG lesion develop within the first months post-transplant and in apparently well-functioning kidneys.

Atypical HUS & Orphan Drugs

Atypical HUS refers to hemolytic uremic syndrome which occurs without E. coli 0157:H7-induced diarrhea as the inciting event. There are many causes of atypical HUS: calcineurin inhibitors, HIV, pneumococcal infection and rare genetic diseases are all on the differential diagnosis. On this latter point (genetic diseases), about 50% of all cases of atypical HUS are caused by mutations in genes which are involved in the complement cascade: specifically, the factor H, factor I, and MCP genes.
Individuals with complement-associated atypical HUS have a relatively high degree of renal problems, and unfortunately there are few therapies other than standard supportive measures which can be used to help treat it. One obvious strategy for treating this disease would be to target the complement cascade. Enter eculizumab (trade name Solaris), a monoclonal antibody against the complement protein C5 (which if you'll recall your complement cascade is at the nexus of both alternative and classical pathways). Already approved for the treatment of other disorders of complement dysregulation (specifically: paroxysmal nocturnal hemoglobinuria), eculizumab was recently granted "orphan status" in an attempt to aid its testing in clinical trials for patients with atypical HUS.

What does "orphan status" mean, exactly? The Orphan Drug Act of 1983 was passed in order to encourage the development of drugs for diseases with a small market, defined as affecting less than 200,000 total individuals in the U.S. The act gives pharmaceutical companies enough incentive to invest in developing drugs for treating rare diseases via granting a prolonged competition-free period and clinical trial tax breaks. There are several nephrology-related diseases which would fall into this category.

Hemoperfusion

The first order of business for today's Renal Fellow Network is to welcome another regular contributor to the mix: nephrology fellow Albert Lam, of Brigham & Women's Hospital. Fresh off the Nephrology boards, Albert will be periodically posting his renal pearls of wisdom for the benefit of renal fellows everywhere.

Today's post is on hemoperfusion. If you've never had experience with hemoperfusion, you're not alone: according to this 2008 Kidney International paper by Tyagi et al, use of hemoperfusion has sharply declined over the past several years, and the indications for its use are infrequent.

What is it, exactly? The hemoperfusion procedure is employed in the treatment of specific intoxications and consists of running a patient's blood through a column containing adsorbent particles to which the toxin binds and are removed from the circulation. These adsorbent particles can either be charcoal (which binds water-soluble drugs) or various polystyrene resins (which bind lipid-soluble molecules). Since dialysis is generally successful at removing most low molecular weight, water-soluble molecules which are not protein-bound, it makes sense that hemoperfusion would be considered only when dialysis is not effective (e.g., high molecular weight, highly-protein bound, large VOD drugs). Some of the drugs traditionally removed via hemoperfusion are theophylline and barbiturates, both of which have fallen out of favor (and thus may account some for the decline in the use of hemoperfusion). Valproic acid compounds can also be effectively removed via hemoperfusion, though dialysis is marginally effective as well. Other factors which have contributed to lower hemoperfusion usage include improvements in dialysis technology (e.g., use of continuous therapies and high-flux membranes) as well as the high expense associated with hemoperfusion cartridges, which cannot be reused. Complications of hemoperfusion include thrombocytopenia, leukopenia, and hypocalcemia.

The differential diagnosis of syndromes involving hypokalemia, metabolic alkalosis, and hypertension

While there are a number of conditions which can cause the combination of hypokalemia and metabolic alkalosis there are a limited number of disease processes which lead to hypokalemia, metabolic alkalosis, AND hypertension. In order to have hypertension in this setting, the pathological disease process must involve increased sodium (and water) reabsorption which leads to volume expansion and elevated blood pressure. The list of these diseases includes:

1. Liddle's syndrome. Autosomal dominant condition caused by a gain-of-function mutation in the epithelial sodium channel (ENaC) which results in increased Na+ reabsorption.

2. Licorice ingestion and the Syndrome of Apparent Mineralocorticoid Excess (SAME). Ingestion of large amounts of licorice (or licorice-containing tobacco or gun) can lead to inhibition of the enzyme 11-beta-hydroxysteroid dehydrogenase, which converts cortisol into the cortisone in aldosterone target tissues (e.g. collecting ducts). Since cortisol has an equal affinity for the mineralocorticoid receptor compared to aldosterone, it would act as the primary mineralocorticoid if it were not converted into the inactive cortisone. The compound in licorice that is responsible for this enzyme inhibitory activity is glycyrrhetinic acid, which also has some mild mineralocorticoid activity. The mechanism is similar in SAME, in which one has mutations in the 11-beta-hydroxysteroid dehydrogenase enzyme that prevent proper conversion of cortisol into cortisone.

3. Renal artery stenosis and renin secreting tumors. Both of these etiologies are the result of elevated production and secretion of renin leading to hyperaldosteronism.

4. Adrenal hyperfunction. This category includes causes of primary hyperaldosteronism, including adrenal adenoma, adrenal hyperplasis, and adrenal carcinoma.

All of these conditions essentially result in or mimic hyperaldosteronism and can be partly differentiated on the basis of the response of the renin-angiotensin-aldosterone system to the disease processes:

Liddle's -- low renin, low aldo
Licorice and SAME -- low renin, low aldo
Renal artery stenosis and renin-secreting tumors -- high renin, high aldo
Adrenal hyperfunction -- low renin, high aldo

Anabolic Steroids as a Cause of Secondary FSGS?

A very interesting article in this month's JASN by Herlitz et al describes a cohort of 10 bodybuilders with chronic kidney disease, making a compelling case that anabolic steroid use is an underrecognized cause of secondary FSGS. The paper is strengthened by the fact that nine of the patients underwent renal biopsy documenting surprisingly aggressive forms of FSGS in many of these patients, including some with the "collapsing" variant of FSGS and others with surprisingly high degrees of interstitial fibrosis and tubular atrophy which are not characteristially seen with secondary FSGS. Perhaps even more convincingly for providing a link between bodybuilding and secondary FSGS, the authors describe a patient whose serum creatinine and proteinuria IMPROVE once the patient's intensive steroid/exercise regimen stops, then gets worse when he returns to this regimen against the advice of his physicians.

There are other health problems already associated with anabolic steroid use--these include gynecomastia, dyslipidemia, testicular atrophy, decreased fertility rates, some forms of hepatotoxicity, neuropsychiatric disorders, and developing a massively enlarged head a la disgraced baseball player Barry Bonds. It seems as if kidney disease can now be added to the list.

As a caveat, however, the authors also point out that there are potential other explanations for how bodybuilding might be linked to FSGS. These individuals were typically on regimens consisting of complicated cocktails of steroids, growth hormone, insulin, protein shakes, diuretics, and other supplements whose content is not carefully regulated. Therefore it remains possible that a substance other than anabolic steroids is the common nephrotoxin amongst these individuals. Furthermore, it's already known that elevated BMI in obese patients can result in secondary FSGS; perhaps their increased lean body mass itself drives the process. High protein diets may expose podocytes to unusually high serum protein levels; could this contribute to toxicity?

One final tidbit I learned from this article: individuals who take creatine supplements (another baseball reference: this is one of the few substances that home run guru Mark McGwire has admitted to taking) may have a falsely-elevated serum creatinine based on the fact that creatine is coverted to creatinine. This limitation can be overcome by measuring a full creatinine clearance in which a 24-hour urine creatinine and simultaneous serum creatinine are used.

DRIVE-ing to the Correct Solution Regarding Anemia Management?

Poll results from last week's question regarding anemia management in the dialysis patient.  Interestingly, there was a fairly strong consensus on this one, with over 75% of individuals electing to give a course of iv iron to the dialysis patient in question, who was anemic despite relatively large EPO doses and a ferritin level of 900.  

The relevant trials to cite here are the DRIVE and DRIVE-II trials, in which anemic dialysis patients with an elevated serum ferritin (between 500-1220 ng/ml) and low transferrin saturation (less than 25%) were randomized to receive either a course of iv iron or not.  After 6 weeks, individuals in the iron group were found to have greater hemoglobin levels than the control group, with no obvious differences in complications between the two groups.  While this result would seemingly indicate that "giving a course of iv iron" would be the correct choice, there are still some reasonable doubters out there.  For instance, this CJASN editorial by Drs. Spiegel and Chertow rationally point out that "the long-term safety of unbridled IV iron administration has never been established."  Although we may find it distasteful as physicians wanted to do something to help our patient correct their anemia, I think a compelling case could also be made for the first answer suggested in the poll--"continue current anemia management."  

Be sure and check out the newest poll question in the right margin!

Low Vitamin D Levels Predict ESRD

Hypovitaminosis D is implicated in a wide variety of disease states, including insulin resistance and diabetes, cancer and cardiovascular disease. A new new study in JASN suggests it may also influence the development of de-novo renal disease.

The investigators integrated data from NHANES and the USRDS database to examine the contribution of low 25 (OH) D levels (less than 15 ng/ml) to the incidence of ESRD over a median follow-up of 9 years. Participants were initially free of kidney disease, with under 0.5% having GFR less than 60ml/min or microalbuminuria at baseline.

Of 13,328 individuals, there were 62 cases of ESRD at follow-up. They observed a 2.6-fold increased risk of ESRD in those with 25 (OH) D levels under 15 ng/ml, after multivariable analysis. Further sub-analysis revealed that almost 60% of the excess risk of ESRD comonly seen in blacks was accounted for by low 25 (OH) D levels in their study.

It is presumed that blacks are predisposed to low vitamin D levels as a consequence of decreased synthesis in the skin due to pigmentation. Being very much at the other end of the skin tone spectrum, I'm not reaching for the multivitamins just yet: I'd like to see some interventional data first.

Nephrotoxic HIV Drugs

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

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

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

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

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

Billy the Kidney Demonstrates Important Principles of Kidney Disease

Last July, for my Dad's 65th Birthday, I managed to somehow convince the Indiana branch of the National Kidney Foundation to loan me their "Billy the Kidney" mascot costume. While it was in my possession, I figured why not get a little creative and use Billy to help illustrate some important manifestations of kidney disease and/or physiology. See if you can guess what each of the following four poses represents (you can scroll down to the bottom for the full answers.)

#1: #2:
#3:
#4:
Answers:
#1 = acute renal failure.
#2 = polycystic kidney disease.
#3 = passing a stone.
#4 = "taking a leak" (in case you can't tell, the vegetable my daughter is handing Billy the Kidney is a leek. Yeah, I know, that's one bad joke.)

Dialysis billing

Why do we write notes in the chart day after day? Why does the chart even exist? In my mind, the main function of the medical chart (and progress notes) is communication: charting allows physicians (and other members of the health care team) to effectively communicate with one another when face-to-face communication is not possible. In recent years, however, it seems as if charting has taken on a different primary function: that of a medicolegal document. Not only does the medical chart serve as the official log for documenting what was and wasn't done correctly (in the event of a lawsuit), but it also serves an important function in billing--in order for a physician to get reimbursed for a particular service, he or she must formally document that service, typically by using key words or phrases, within the written chart. Failure to do so correctly can result not only in a failure to get paid hard-earned money, but can even result in allegations of billing fraud.

Thus, it's important to know the dialysis billing codes. Despite its central importance, the details of billing weren't really emphasized to me during either my residency or my fellowship training. Here are a few of the important billing codes and important billing issues related to nephrologists, focusing primarily on the relevant "CPT" (or "Current Procedural Terminology") codes for dialysis. If there are any seasoned nephrology vets out there, please feel free to make comments or clarifications, as I'm just personally discovering the coding game:

• Inpatient Dialysis Codes. The main issue to be aware of here is that in order to get reimbursed for supervising a dialysis session, the attending physician must be physically present while the patient is undergoing the dialysis procedure. Seeing the patient beforehand and writing out the prescription is not enough--you have to be present while the patient is hooked up to the machine. I have been advised to write something like, "The patient was seen and examined while on dialysis," as well as being careful that your date & time on the note is consistent with the patient's time on dialysis. Obviously, this applies only to attendings and not to fellows. The standard inpatient hemodialysis code is the "90935". If you see a patient in the morning and then their status changes such that they now require dialysis, you can still get credit for the procedure by billing a "90937" (again, as long as the nephrologist is present for part of the dialysis procedure). A separate set of codes ("90945" for single visit and "90947" for multiple visits) is used for other dialysis procedures such as peritoneal dialysis; I believe this code can also be used for coding CVVHD.

• Outpatient Dialysis Codes. A list of the major outpatient dialysis codes can be found here; they are generally submitted monthly: the main ones for adult dialysis are "90960" (for 4 face-to-face visits per month), "90961" (for 2-3 face-to-face visits per month), and "90962" (for a single face-to-face visit per month). Separate codes exist for patients who are dialyzed for only a few days out of the month, or for supervising home hemodialysis ("90966").
  

The process of nephrology billing is sufficiently complex that the Renal Physicians Association offers full-day "Coding and Billing Seminars" around the country. The discussion above does not even go into the intricacies of billing for individual injectable medications or all the important disease-specific codes (e.g., ICD-9 codes for CKD, hypertension, etc) which are routinely encountered in outpatient clinical practice.

Link Between CMV Status & EPO Requirements

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

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

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

SGLT Inhibitors

A promising new class of oral hypoglycemic agents for type 2 diabetes, the SGLT inhibitors, are on the horizon. As they work on the kidney, and potentially have renal side effects, it may be helpful to review them.

These agents work by inhibiting the SGLT2 glucose transporter found in the S1 segment of the proximal tubule, responsible for 90% of glucose reabsorption in the kidney. They work by causing dose-dependant renal glycosuria, lowering both plasma glucose levels and insulinemia in animal models. Agents have the suffix -gliflozin, and examples include dapagliflozin and sergliflozin. Here's a recent review.

Interestingly, humans with loss-of-function mutations in SGLT2 live into adulthood, but experience systemic hypotension with markedly elevated renin levels, hypernatremia and metabolic alkalosis. This seems to be driven by renal sodium wasting occurring in association with glycosuria. These phenomena could also possibly occur as side effects of these drugs. Whether this side effect is a blessing (through improved BP and volume control) or a curse (through an adverse interaction with ACE inhibitors) remains to be seen. But with over 20 prototypic agents in the drug development pipeline, we'll definitely be hearing more about them.

Steroids for AIN? Poll Results

Very interesting results from last week's poll, in which the question asked was essentially, "Do you believe that steroids are effective in the treatment of AIN?"  The vote was generally split 50-50; that is, about half of individuals felt that removal of the drug and conservative management was the correct decision and about half of individuals felt that some form of steroids should be used.  

This topic is interesting to me because I have run into several experienced nephrologists, whose opinion I really respect, who are adamant that steroids SHOULD be used in the treatment of AIN, despite the conflicting data.  One of the major difficulties in evaluating this question clinically is the relative lack of randomized controlled trials, as well as the general trend to diagnose AIN based on clinical grounds rather than a confirmatory renal biopsy.  Recently,  a 2008 retrospective analysis in KI by Gonzalez et al demonstrated a correlation between a delay in steroid treatment for AIN and the final serum creatinine, causing the authors to suggest that if steroids are going to be used, they should be used relatively early in the disease course.

Check out the latest RFN Poll of the Week in the right margin!

Opiates in advanced renal failure

I was taught the rule of 6's when it came to using opiates in dialysis patients:

• they're metabolized by hepatic glucuronidase to 6-glucurinides (e.g. morphine 6 glucuronide or M6G)
• these metabolites are renally excreted, increasing the half-life to 6 times that of the parent compound in ESRD
• peak toxicity may not occur for over 6 hours (or at 6 am while you're on call) as M6G occurs in both hydrophilic and lipophilic forms, and it takes time for the latter to cross the blood-brain barrier and acculmulate in the CSF. Opiate toxicity should be your first thought in any hypoventilating dialysis patient.

The worst offenders are codeine and morphine, and to a lesser extent oxycodone and hydromorphone. Not all opiates behave like this though, and the following three are probably safest:

• Fentanyl has no active metabolites and appears to be well tolerated.
• Tramadol is a non-narcotic analgesic with some effects at the mu opioid receptor. It's usual half-life is 5 hours, increasing to ten in ESRD. Max. dose of 50mg bid. Watch out for serotonin syndrome with SSRI's
• Methadone does not appear to accumulate at all in renal failure, as observed in drug addicts with CKD and ESRD, and appears safe to use.

Finally, the same pharmokinetic properties that render these 3 agents "safe" in ESRD also make them un-dialyzable, so they should be up-titrated cautiously.

Restless Legs Syndrome in Dialysis Patients

Restless legs syndrome (RLS) is one of the potential neurologic complications associated with CKD or ESRD, though it can also occur independently of kidney dysfunction, with some cases of familial transmission documented (though no gene has yet to be identified). The 2003 NIH criteria for the diagnosis of RLS are the following:

(1) the urge to move the legs, usually with unpleasant sensations.
(2) the appearance of symptoms during inactivity or rest.
(3) relief of symptoms with movement.
(4) worsening of symptoms in the evening or at night.

The mechanism of RLS is unclear, but many signs point to (a) the dopaminergic system (dopamine agonists, such as ropinirole, have been observed to successfully treat some individuals with RLS), and (b) iron status (iron supplementation also appears to have some benefit in treating RLS in individuals with depleted iron stores--a problem which may be accentuated in dialysis patients). In addition, there is some suggestion that inadequate dialysis may be a cause of RLS; this study by Kim et al showed that pre-dialysis BUN is associated with RLS symptom severity.

Thus the workup for dialysis patients with RLS symptoms should include an assessment of dialysis adequacy, review of anemia/iron labs, review of the medication list for drugs which have been associated with RLS (certain antidepressants and antipsychotics have been implicated), and any evidence of a positive family history of RLS.