Pearls for Boards

1) Icodextrin sometimes causes a desquamating rash on the palms and soles.

2) Sirolimus, five side effects to watch 1) Poor wound healing 2) Lung toxicity 3) Hyperlipidemia 4) Proteinuria 5) Anemia/Thrombocytopenia.

3) Classic EM finding in post infectious GN: Large subepithelial hump shaped deposits.

4) Conivaptan is both a V2 and V1a antagonist - as such, contraindicated in cirrhosis were V1a agonists are used for variceal bleeding.

5) Eosinophilic peritonitis is not uncommon when breaking in a new PD catheter.

Aquaretics and PCKD

One of the big stories at the ASN this year was the announcement of the results of the TEMPO trial which were simultaneously published in NEJM. It has been known for some time that ADH is implicated in cyst growth in patients with polycystic kidney disease (PCKD) and that suppression of ADH release with high water intake or vasopressin receptor blockade reduces cyst growth in animal models. The TEMPO trial was a 3-year, multicenter controlled trial involving 1445 patients with PCKD who were randomized to receive tolvaptan (a V2-receptor antagonist) or placebo. The primary outcome was the rate of change in total kidney volume while the rate of CKD progression was a secondary outcome.

There was a lower rate of kidney growth in the tolvaptan group (2.8% per year vs. 5.5% per year) and a slower decline in renal function also. These are fantastic results and they should be celebrated, especially considering the disappointment surrounding bardoxolone. However, there are a couple of significant issues which should be considered. All of these patients had normal renal function at the time of entry into the study. The majority of these would progress very slowly to end stage and the cost of treatment with tolvaptan over this period of time would be enormous. Also, about 23% of the participants dropped out due to adverse effects (although, it should be said that 14% of the placebo group also dropped out). The most important side effect was liver toxicity.

So the question arises – who are the patients that will benefit most from vaptan treatment. As the accompanying editorial states – “the development of comprehensive criteria for aquaretic treatment and appropriate patient selection are needed”.

So maybe a recent series of papers from a group in Holland may help provide the answer. Vasopressin is difficult to measure in vivo because of its short half-life and tendency to bind to platelets. However, one of the components of its precursor, copeptin, is stable in plasma and can be used as a surrogate for the serum vasopressin concentration. Last year, this group published a paper which found that, in a group of 102 patients with PCKD, serum copeptin levels were associated with markers of disease severity such as kidney size, GFR and albuminuria. The group published two follow-up longitudinal studies (using historic samples from previous studies) in NDT and AJKD. In a group of 79 patients, higher baseline copeptin levels were associated with more rapid decline in renal function over 11 years follow-up. 8 of the 9 patients that started hemodialysis over the course of the study had copeptin levels above the median. It should be pointed out that baseline copeptin levels were higher in patients with lower GFR at the time of entry to the study and this could have biased the results.

The last paper looked back at 241 patients with normal baseline renal function who were included in a longitudinal study of cyst growth (and measured GFR!) In these patients, higher baseline copeptin levels were associated with a greater change in kidney volume over 8 years follow-up. After full covariate adjustment, there was a trend towards a greater decline in renal function in the higher copeptin group but this was not statistically significant. Again, however, patients with larger kidneys at baseline also had higher copeptin levels. Because of the size of the molecule, there may be some element of reduced clearance in patients with lower GFRs and this could explain some of the differential. Higher copeptin levels have also been noted in patients with other renal diseases so this is not entirely specific. This needs to be further studied.

Still, although not definitive, these studies provide some rationale for a potential means of stratifying patients with PCKD and certainly give a route for further investigation. It would be interesting, perhaps, to go back and measure baseline copeptin levels in the patients in the tolvaptan study to determine if there was a difference in response to therapy based on this promising biomarker.

Obituary from the NYT.  In 2010, RFN on the passing of Ronald Herrick.

Miracle Drug - Part 2

In a previous post, we discussed the dangers of subgroup analyses. Specifically, performing increasing numbers of post-hoc subgroup analyses increases the risk of a type 1 error while the inevitable reduction in numbers tested in subgroup analyses decreases power and increases the risk of a type 2 error.

This is a particular problem in nephrology where there is a lack of randomized trials and a lot of our information is gleaned from subgroup analyses of trials that were never intended to specifically test patients with CKD. A paper was recently published in CJASN which examined the issue of subgroup analysis in the nephrology literature and suggested some potential guidelines for reporting:

1. Plan subgroup analyses during the study's design period

2. Limit the analyses to variables where a plausible hypothesis exists for why there might be a difference between groups

3. In the methods section, list the pre-specified analyses and explain the rationale for each analysis

4. Do not report subgroup analyses in the abstract

5. Use statistical tests for interaction and report effect estimates (confidence intervals rather than p-values)

6. Avoid over-interpretation of subgroup analysis results, explain that this is hypothesis-generating rather than definitive and emphasize the overall study results

The idea is to prevent fishing - performing multiple post-hoc analyses until one is found that is positive. Technically, if one is going to do this, there should be a correction for multiple statistical testing but this is rarely done. The authors of the review examined published randomized trials in 4 major journals and found that about 1/3 of nephrology papers published subgroup analyses (which was actually below average). However, more than 3/4 of these had issues with the analysis including the lack of pre-specified subgroups and inappropriate statistical testing. 

The take home from this for the general audience who will not necessarily be performing these analyses is to carefully examine any trial that makes far-reaching claims based on a subgroup analysis. Remember that in the majority of cases, the trials were never designed to look at these subgroups and that these results should not be regarded the same way as the primary results of the papers. Similarly, a negative result in a subgroup analysis should be examined carefully to determine if the study had sufficient power to come to this conclusion. This is certainly not to say that they should never be done. Some extremely valuable information has come from these analyses and one should never assume that all groups will respond in the same way to the same treatments.

Pearls for Boards

1) Monoclonal Immunoglobulin Deposition Disease breakdown - 80 to 90% LCDD, 10 to 20% LHCDD, <5% HCDD.

2) Small studies suggest tamoxifen and steroids may be of benefit in management of Encapsulating Peritoneal Sclerosis in patients on PD.

3) Sodium restriction helps lower the risk of calcium nephrolithiasis by increasing proximal tubular uptake of sodium and subsequently calcium.

4) The age at presentation of anti-GBM disease has a bimodal distribution with a male predominance in younger patients and a female predominance in older patients.  More severe disease with lung involvement is more common in young patients while isolated GN is more common in older patients.

5) Hypothermia leads to potassium shift into cells and serum hypokalemia.

Does that taste bad? - Part 2

Following on from yesterday's post about turtles who may have a taste of urine in their mouths, here's an interesting historical diversion about doctors who, in the past, intentionally drank urine to diagnose disease. An article in Scientific American gave us this picture of a "urine wheel" which, by correlating the taste, smell and appearance of the urine, was a valuable diagnostic tool in the 16th century. The classic diagnosis associated with tasting the urine was of course diabetes but it is by no means the only one. 

Edible geography collected various other urine wheels.

Picture originally from Nature.

Does that taste bad?

Better known as a delicacy in the Far East, the Chinese softshell turtle has generated some interest in the Nephrology world because of its unusual means of urea elimination. A paper was recently published in the Journal of Experimental Biology in which the authors described the process of urea excretion in these interesting animals. The primary habitat of the turtle is seawater, and saltwater marshes and swamps. As a result, most of the water in that environment is hyperosmolar such that eliminating urea via the kidneys could lead to excessive water losses. It had been previously noted that the turtles have a tendency to submerge their heads in water for prolonged periods. The researchers attached plastic bags to the cloacae of the turtles but, to their surprise, found that the urea concentration in the water where they submerged their heads was higher that that of the collected urine. 

The turtles have buccopharyngeal villiform processes in their mouths that contain active urea transporters. They take water into their mouths and spit it out again in order to excrete urea waste. A transporter was isolated from the buccal mucosa that had a 70% homology with mouse and human UT-A2. This transporter was not present in the kidneys of the turtles indicating a lesser role for the kidneys in urea transport. The average urea concentration of the saliva was 36mmol/L as opposed to 2.4mmol/L in the serum. After an IP injection of a urea load, the serum concentration increased to 45mmol/L while the saliva concentration increased to an impressive 614mmol/L.

This evolutionary adaptation may have allowed them to invade this hostile environment. 

Conference Review: Home Dialysis University

It doesn't take much to get me to take a trip to San Diego so when the opportunity came up to attend this year's Home Dialysis University conference I booked my flight.  Having lived in San Diego for many years prior to moving to the Bay Area I took the opportunity to both check out this great conference and stay and visit with old friends.

The conference (formerly known as Peritoneal Dialysis University) now has significant content going over home hemodialysis therapies with much of this being delivered by Brent Miller who was one of the FHN daily investigators and part of the ongoing FREEDOM study.

The conference registration and up to $350 in hotel and travel are covered for fellows by a grant from the International Society of Peritoneal Dialysis.  The conference and accommodations were at the Westgate Hotel in the Gaslamp district.  Great location and high marks for tasty breakfast, lunch and frequent snacks (all at no additional cost!)

Conference size was small, under 20 people so lots of opportunity to interact with the faculty and other attendees. Also a short conference, one full day and two half days.

John Burkart from Wake Forest gives a great lecture on how PD and HD work in terms of small and other solute clearance and reviews the uses and limitations of Kt/V.  He also gives a very practical lecture on the financial considerations related to home dialysis.  Anjali Saxena (one of my attendings who is the PD director down at the Stanford affiliated Santa Clara Valley Medical Center) covers PD access issues, the challenges that face the long-term PD patient and the infrastructure requirements for starting your own home unit.  Joanne Bargman from Toronto does some great case based discussions surrounding commonly encountered PD issues.

One of the highlights is the hands-on demonstration session were home dialysis RNs actually do a walk through with a PD cycler and a NxStage machine. Very informative.

An area where many fellows unfortunately have limited exposure is the nuances of the dialysis prescription writing for the NxStage system.  Brent Miller gives a really nice talk going over the details of this.  Lots of nice compare and contrast examples to conventional HD to put things in a more familiar context.

At least as of this writing, they haven't announced when the 2013 fellows conferences are going to be held so stay tuned to their website for dates.  In past years they've had sessions in several locations on several different dates so hopefully you'll find something that will fit your schedule.

I again tried my best to keep up a solid twitter feed of interesting points for RFN which you can find here with all the tweets indexed under #HomeDialysisU.

Spare the Chloride

Fluid therapy is essential in ICUs and not surprisingly there is still much controversy about which fluid to use, how much and when. Nephrologists often roll their eyes at other subspecialty's preferences, e.g. surgeon's preferences for Ringers, citing the risk of hyperkalemia in renal failure patients given Ringers. I learned that normal saline is the preferred agent unless there is a special consideration such as acidemia necessitating alternatives. Now chloride, the partner of sodium that gets considerably less attention most of the time, enters the stage.

Yunos et al in JAMA suggest that too much of chloride increases acute kidney injury (AKI) episodes in tertiary ICUs and increases the need for renal replacement therapy (RRT) but does not affect mortality.

The physiological rationale for the detrimental effect of chloride on the kidney is described as vasoconstriction mediated by chloride in dog experiments and a possible role of tubuloglomerular feedback mediated vasoconstriction as well as decrease in GFR caused by increased distal chloride delivery. Furthermore they cite thromboxane mediated vasoconstriction caused by chloride and enhanced responsiveness to vasoconstrictor agents as possible physiological sequelae of chloride administration.

The authors of the JAMA article conducted a prospective, open-label sequential pilot study of patients admitted consecutively to the ICU. Initially patients were treated with chloride-rich IV fluids (0.9% saline, 4% succinylated gelatin solution or 4% albumin solution) and after that initial control period a chloride-restricted strategy was implemented with lactate (Hartmann solution), a balanced solution (Plasma-lyte 148) or chloride-poor 20% albumin as preferred agents.

The results were a lower increase in serum creatinine levels and fewer episodes of RRT in the chloride-restricted group but no differences in mortality, hospital or ICU length of stay or need for RRT after discharge.

How does this study affect our choice of ICU fluids? Certainly, these results are hypothesis generating and important but need to be viewed as preliminary given the design of the study. An accompanying editorialby Waikar mentions the Hawthorne effect as potential major concern. Clearly these important preliminary data need follow up in a controlled prospective trial. 

Posted by Florian Toegel

Pearls for Boards

1) Alkaline urine encourages calcium phosphate nephrolithiasis. Three predisposing factors to watch for - 1) distal RTAs 2) Acetazolamide 3) Topiramate.

2) IgA nephropathy, common in Asians and Native Americans, rare in African Americans.

3) Stay alert for triphasic pattern of water disturbance post neurosurgery or cerebral trauma - hypernatremia, hyponatremia and finally hypernatremia.

4) Long term PPI use can result in hypomagnesemia, hypocalcemia and hypokalemia.

5) Renal Malignancy Syndromes: Tuberous sclerosis - Angiomyolipomas and rarely RCC, Von Hippel Lindau - RCC and Pheo, Birt Hogg Dube Syndrome - chromophobe RCC.

Image of the Month - GN with a twist

A man in his 30s with no significant medical history presented to the ED following a fainting episode. Routine screening found an abnormal creatinine, hematuria and proteinuria. Serological work-up including complements were negative. In view of a slowly increasing creatinine and 3g of proteinuria, he was referred for a renal biopsy.

A low power view of the renal cortex revealed diffuse fibrosis and interstitial inflammation. There was evidence of focal sclerosis with occasional sclerosed glomeruli.

A high power view of a typical glomerulus revealed mesangial expansion and proliferation with normal-appearing capillary loops. There were no cellular crescents and some glomeruli had evidence of focal sclerosis.

Examination of the renal vasculature revealed severe arterial sclerosis and moderate arteriolar sclerosis.

Not unexpectedly, the EM found extensive mesangial deposits with no sub-endothelial or subepithelial deposits and a normal appearing basement membrane. The podocyte morphology was also well preserved.

Top on the list of differentials in this patient was IgA nephropathy and as expected, the immunofluorescence revealed extensive mesangial staining for IgA. At this point, many pathology labs would leave it at this and make a straightforward diagnosis of IgA. However, our lab can't just leave it alone and generally also routinely stains for immunoglobulin light chains. Typically in IgA nephropathy, lambda light chains are more prominent than kappa light chains on IF but the difference is not marked.

 

In this case, there was almost no staining for kappa and marked lambda staining. This suggests that a monoclonal IgA is present. The serum immunofixation was negative and so far, a bone marrow biopsy has not been done.

Monoclonal IgA is rare and has only been reported in case series in the literature. It is often accompanied by a positive SPEP and is thought, at least in some cases, to be related to a clonal expansion of B-cells. About 20% of myeloma is IgA but this is rarely associated with deposition in the kidney (although this may be due to a lack of biopsies). Anecdotally (speaking to my colleagues), this form of IgA nephropathy is relatively aggressive with rapid progression. This has not been formally studied. The question that arises is how to treat this. Should it be treated with rituximab/steroids/velcade? This is relatively toxic treatment and in the absence of an abnormal bone marrow or serum evidence of a monoclonal gammopathy, it is difficult to make this argument. However, one would wonder about the likelihood of recurrence after renal transplantation. 

In this case, the decision has been made to hold off on aggressive treatment for the moment with regular monitoring of the serum. This is a fascinating case and just goes to show how diverse a condition like IgA can be. 

(Click on any image to enlarge)

REMS in Renal Disease

In 2007, the Food and Drug Administration (FDA) was granted the authority to require pharmaceutical manufacturers to develop risk evaluation and mitigation strategies (REMS), if deemed necessary. This was made possible by the FDA Amendment Act, which also authorized the FDA to declare a medication product as misbranded and to forbid the utilization of interstate commerce for that product, as well as to financially penalize manufactures of REMS-issued medications if they do not comply with the requirements. REMS are intended as a way to mitigate potentially serious risks associated with certain pharmaceuticals and to maximize the benefit of these high-risk medications. A number of different elements can be employed to achieve the risk mitigation that is intended with medication-specific REMS, which include a medication guide, a communication plan and/or Elements to Assure Safe Use (ETASU). 

 • A medication guide is patient-directed educational material with a goal of increasing awareness on the safe use of the pharmaceutical product. Reasons why medication guides would be required include if access to this educational information has the potential to influence factors including serious medication adverse events, the patient’s decision to use the pharmaceutical product and patient compliance. A medication guide must be given to the patient each time the drug is dispensed, including refills.

• A communication plan is another element of REMS and is a means of providing education on the safe and appropriate use of pharmaceutical products to health care providers. A communication plan is implemented by the manufacturer and involves contacting healthcare providers or professional societies, usually via letters, to encourage compliance with the REMS elements. 

• An ETASU may be required as parts of REMS if the FDA determines the other elements are incapable of guaranteeing the safe use of the medication. An ETASU may involve attainment of special certification of prescribers and pharmacies that are involved with the dispensing of these pharmaceutical products, or may restrict the use of these medications only to patients who are enrolled in registries, receive treatment in specific settings or with documentation of certain safety requirements.

In transplantation, the costimulation inhibitor, belatacept (Nulojix®), has required a medication guide and a communication plan for its REMS since June 2011. In September 2012, the mycophenolic acid derivatives (mycophenolate mofetil [CellCept®] and its generic products and enteric-coated mycophenolic acid [Myfortic®]), which are T-cell proliferation inhibitors, were issued a REMS requirement that included a medication guide and an ETASU. In general nephrology, there are REMS in place for the erythropoietin-stimulating agents (i.e. epoietin alfa [Epogen® and Procrit®], darbepoietin [Aranesp®] and peginesatide [Omentys®]). The REMS epoietin alfa products and darbepoietin each contain a medication guide, communication plan and ETASU. However, the ETASU is meant only for those patients using one of these agents for anemia associated with malignancy. The peginesatide REMS only contains a communication plan. It is vital for nephrologists to realize that there may be other medications that prescribe on a routine basis in your practice that contain a REMS, besides the ones listed above. 

It is important to keep in mind that the overall goal of REMS is to increase patient safety in regards to the use of high-risk pharmaceutical products. The FDA tries to limit the burden that REMS puts on health care providers and patients. However, a result of REMS may be the decreased utilization of specific high-risk medications to avoid the REMS requirements. This is an unfortunate and unintended consequence of a program that was created to increase the safe and effective use of medications. The usage patterns of medications the FDA has determined require a medication guide, communication plan, or ETASU, should not be altered to avoid the extra work associated with these elements of REMS. 

Sara Rostas, PharmD, PGY1 Pharmacy Practice Resident
Steven Gabardi PharmD, FCCP, BCPS, Organ Transplant Clinical Specialist 

Pearls for Boards

1) Topiramate - Watch for non-gap acidosis, nephrolithiasis and hyperammonemia.

2) Jak2 - the intracellular kinase activated by the binding of Epo to the Epo receptor.

3) Live vaccines are contraindicated in kidney transplant recipients – these include MMR, Varicella, Yellow fever and BCG.

4) Liddle's, the opposite of Pseudohypoaldosteronism Type I - Gitelman's, the opposite of Pseudohypoaldosteronism Type II (also known as Gordon's syndrome).

5) Myeloma cast nephropathy - distal intratubular casts, Light Chain Fanconi Syndrome - proximal intracellular crystals.