Thursday, December 30, 2010

Obituary of first kidney donor- Ronald Herrick

Spare a thought today for Ronald Lee Herrick who died on Monday at age 79. In 1954, his identical twin brother, Richard, had end-stage kidney disease with little prospect of long-term survival. Dr Joseph Murray, a pioneering surgeon from the Brigham Hospital in Boston, performed the first successful renal transplant from Ronald to his brother thus saving his life and proving that transplantation was a viable treatment for chronic renal disease.

It's hard to imagine these days how revolutionary this was. In order to ensure that the kidney would not be rejected, the doctors first had to prove that they were actually identical twins. This was done using the science of fingerprinting and by performing skin grafts to demonstrate that they would accept the graft. Then, as now, there were concerns about the long-term effects on the donor and no-one was certain that the kidney would function after transplantation.

The recipient, Richard, went on to marry one of the nurses who took care of him in the hospital and fathered two girls before he died 8 years later. Ronald worked as a teacher and a farmer and passed away this week. Dr Murray received the Nobel Prize for his work and still lives in Massachusetts at the age of 91.

Here is a 2004 NPR report on the first transplant where they interviewed Dr Murray and Mr Herrick.

Tuesday, December 28, 2010

More insulin!

Peritoneal dialysis solutions containing glucose polymers are becoming more popular, particularly in patients on APD who tend to retain fluid during their daytime fills. The rationale for their use is that they lead to a reduced absorption of the solute with more ultrafiltration. The commonest fluid used currently is icodextrin which comes in a 7.5% solution and is generally regarded as being safe and well tolerated albeit with a slightly increased incidence of cutaneous reactions compared with traditional, dextrose-containing solutions. However, there is one side effect which is potentially life-threatening if unrecognized.

A 60-year-old patient on PD with a history of poorly controlled diabetes presented to the ED with nausea, slurred speech and drowsiness. Fingerstick blood sugar was elevated at 360mg/dl. He was started on an insulin infusion and had a CT brain that had no acute changes. Despite the insulin infusion, his blood glucose remained elevated and a simultaneous blood sugar was sent to the lab which came back at 24. He was immediately given a glucose bolus and his symptoms resolved.

Icodextrin is not metabolized in the peritoneum. However, it can cross into the systemic circulation at which point it is metabolized to maltose. Some commercial blood sugar test strips cannot distinguish between glucose and other sugars which, under normal circumstances, are not present in large amounts in the blood. Specifically, strips that contain a reagent called glucose dehydrogenase with coenzyme pyrroloquinolinequinone (GDH PQQ) will give falsely elevated blood sugar readings in patients who use icodextrin. Reagent strips that use glucose oxidase and glucose hexokinase (GDH-NAD, GDH-FAD) do not detect other sugars and thus are more accurate in patients receiving icodextrin. There have been a number of severe adverse events reported to the FDA related to this side-effect and at least one death.

Interestingly, this is not limited to PD patients. A similar problem has been noted with some immunoglobulin preparations which also contain maltose. Other sugars which may cause falsely elevated blood glucose readings include galactose and xylose. Thankfully, my institution uses GDH-NAD so this has not been an issue but it is something to be aware of in PD patients with elevated blood sugars and inconsistent symptoms. See this case report from the BMJ for details.

Saturday, December 25, 2010

Top nephrology-related stories of 2010


2010 was a busy year in field of nephrology.  RFN covered a wide variety of topics over the last year.  Several news stories stood out.  This is by no means a complete list of all of the major news stories.  Feel free to add to this list in the comment section below.  I will summarize each of these studies/stories below in increasing order of votes received in our  year-end poll (votes for story/total votes).

8. Results from renal sympathetic nerve ablation for hypertension presented at AHA (3/126)-  The much awaiting 6-month results from the Australia based SYMPLICITY HTN2 trial were presented at AHA and published in the Lancet.  This was a randomized trial of 106 patients with refractory hypertension assigned to either catheter-based renal sympathetic nerve ablation + medical management vs. medical management alone.  BP dropped by 32mmHg systolic and 13mmHg diastolic in the treatment group compared to 1mmHg and 0mmHg in the control group and were sustained over the 6-month followup period.  Minimal side effects were observed.  This is similar to the proof of principle study that was discussed in detail on RFN.  It will be interesting to see how these results hold up over time.  Offering renal sympathetic nerve ablation to patients with refractory hypertension could prove to be nice therapeutic option if this procedure is shown to have good results over the long term.  Right now all we have is the 6-month data which do, however, look encouraging.   

8. Kidney transplantation in HIV+ patients published in NEJM (3/126)-  Kidney transplantation for individuals with concomitant ESRD and HIV has been a controversial topic. This study, reviewed on RFN will likely put some of these issues to rest.  This was a prospective multi-center trial following 150 HIV+ transplant recipients.  The group was followed for up for a median of 1.7 years.  They found patient survival rates were similar to the general population and graft survival rates were somewhere in between the general population and a high risk population of patients receiving kidney transplants.  These are encouraging results and pave the way for opening up transplantation for this group of patients.

7. Propublica article on chronic hemodialysis (5/126)-  On Nov. 7th Propublica reporter Robin Fields published "God Help You. You're on Dialysis" in The Atlantic.  This story chronicles the ongoing saga of chronic hemodialysis in the United States from when congress granted comprehensive coverage for all patients with ESRD in 1972 to present.  Robin interviewed several patients and investigated several dialysis centers in her multi-year investigation into this topic for which she highlighted several deficiencies.  The Propublica piece is a timely article as it comes on the heals of the most ambitious change in funding for chronic dialysis care and our #1 story of the year- "medicare bundling for dialysis".  The story has garnered reactions from several entities including CMS chief  Barry Straube (listen to his interview on NPR), dialysis giant DaVita and several others (click here for a comprehensive list from the Fix Dialysis blog).   


6. Two Rituximab trials (RITUXIVAS and RAVE) for ANCA-vasculitis (7/126)-  These two trials compared rituximab (anti-B cells antibody) vs. IV or oral cyclophosphamide respectively during the induction phase of ANCA-vasculitis and were published simultaneously in the NEJM in July of this year.  Dr. Falk wrote an excellent editorial in regards to these trials here.  Both trials although with significant differences in the study design showed that rituximab was efficacious in inducing remission.  However, no significant differences were seen in toxicity parameters between the groups (a result that was surprising).  Although these results are encouraging, only 12-month (in RITUXIVAS) and 6-month (RAVE) remission rates are presented.  Long term data on remission will be important before rituximab will be considered first line.

5. The Frequent Hemodialysis Network Trial published in NEJM (10/126)-  This was one of four positive trials presented at ASN Renal Week this year.  Thrice-weekly dialysis has been the mantra of dialysis care in much of the world and the US.  Several observational studies have been performed comparing thrice-weekly with longer dialysis duration (click here or here for reviews of these studies).  These studies have shown that longer duration dialysis can improve a variety of parameters.  As such, quotidian (or daily) dialysis has begun to gain increased popularity in the dialysis community. However, large randomized trials are lacking.  This trial randomized 245 patients to either frequent (six-times per week, 1.5-2.75hrs/day) or standard (three-times per week, 2.5-4hrs/day) dialysis.  The patients were followed for 1 year.  Frequent dialysis was significantly superior on both co-primary outcomes: The composite of death or change in left ventricular mass as well as the composite of death or change in RAND Physical Health Composite from the SF-36.  Secondary outcomes of hypertension and hyperphosphatemia were also improved.  This is an important trial that will likely impact how dialysis will be offered to patients with ESRD.  How these results will be incorporated into the new CMS model will be interesting.     

4. APOL1 gene variants reported in Science are associated with increased risk of renal disease in African Americans (16/126)-  The surprise story of 2010 was definitely the publication in Science that two APOL1 gene variants are associated with an increased risk of renal disease in African Americans.  All of the attention had been focused squarely on MYH9 variants and now it looks as if the next door neighbor (at least genetically) might be even more important.  This again was covered by RFN.  To summarize the researchers found that the same two variants of the APOL1 gene that are associated with the increased risk of renal disease may also protect against African sleeping sickness (Trypanosoma brucei rhodesiense).  I'm sure we will hear more on this story as well.

3. SHARP trial results released at ASN showing statin/zetia benefit in CKD (19/126)- Another big surprise at ASN renal week this year were the results from the long-awaited SHARP trial.  With all of the negative or neutral studies looking at statin therapy in ESRD patients it was quite the surprise that this was a positive study.  SHARP compared the combination of ezetimibe/simvastatin to placebo in  9,438 patients with CKD (1/3 of which were on dialysis). The investigators found that patients taking ezetimibe/simvastatin had a significant (p=0.0010) 16.1% reduction in the incidence of first major vascular event (nonfatal MI or cardiac death, stroke, or revascularization).  Furthermore, they did not find a difference in adverse events including rhabdo, cancer, muscle cramps etc.  No differences were seen in renal outcomes in patients not on dialysis at the beginning of the trial as well.  Full results of the trial are not yet published.  Read this summary of the results from CardioBrief.    

2. The IDEAL trial comparing early versus late initiation of dialsyis published in NEJM (21/126)- Coming in at #2 is the IDEAL Trial comparing early versus late initiation of hemodialysis.  This trial was discussed in detail on RFN.  When to start a patient on dialysis is a frequent clinical conundrum in nephrology and this trial shed some light onto this topic.  Researchers from Australia and New Zealand randomized 828 patient to either start dialysis early (eGFR of 10-14 regardless of uremic symptoms) or late (eGFR of 5-7 or uremic symptoms were present).  No differences were seen in the primary or secondary outcomes after an average of 3.5 years of followup.  Although, this trial doesn't definitively answer this question, it does allow for more comfort when following a patient with with advanced CKD.

1. Medicare bundling for dialysis (42/126)-  The #1 nephrology-related story of the year and likely for the last 2 years is "medicare bundling of payments for chronic dialysis".  This is scheduled to begin on January 1, 2011.  Much apprehension and anxiety about these changes have been evident over the last 2 years.  CMS released the final report on July 26th of this year.  Reaction to these rules have been covered by DSEN and ASNMedicare will provide a single payment that covers all renal dialysis services—including drugs and diagnostic laboratory tests—to dialysis facilities for each dialysis treatment.  Furthermore, an algorithm adjusting for patient demographics and a quality incentive program (QIP) will be put into place.  How these changes affect the care of patients on dialysis will be under intense scrutiny after the changes are put into place.  CMS plans to undertake a monitoring campaign to see how these changes impact patient care.  I'm sure this topic will be high on the Top Stories list of 2011 as well.  

As you can see, quite a busy and exciting year in the world of nephrology in 2010.  RFN will continue to provide coverage of all-things-renal in 2011.  Thanks to all of our contributors and readers for keeping the site going strong in 2010.  2011 is promising to be an even better year for nephrology and RFN.

Thanks for supporting RFN in 2010.  We'll be back in January.

Thursday, December 23, 2010

What causes IgA Nephropathy?

IgA nephropathy is the most common cause of glomerulonephritis in countries where renal biopsies are commonly performed. See a previous post on the wide variety of presentations with this syndrome and this review. But what do we know of the actual pathogenesis of this condition?

IgA has two subclasses – IgA1 and IgA2, the latter lacks a specific amino acid sequence comprising the hinge region. The absence of this region confers more resistance to bacterial degradation. The majority of IgA in humans (95%) is monomeric, produced by plasma cells and freely circulates in the bloodstream. The remainder is produced by mucosal lymphoid cells and secreted in a dimeric form. The half-life is usually 4-5 days, with IgA molecules undergoing rapid hepatic metabolism.

IgA renal lesions characteristically involve IgA1 deposition in the mesangium. Therefore, research has focused on identifying abnormalities in the hinge region, unique to this sub-class. In normal circumstances the hinge region undergoes glycosylation of serine and threonine molecules, followed by the incorporation of galactose and sialic acid.
However, abnormalities that result in reduced glycosylation can predispose to self-aggregation of IgA1 molecules to form large complexes. These complexes can bind to Fc receptors on immune cells, causing cleavage of the receptor from the cell and formation of a larger complex. Hypo-glycosylation may also lead to exposure of certain residues in the hinge region that are immunogenic in themselves.

Circulating polymeric IgA can also bind IgG, forming circulating immune complexes. The resultant molecules can then deposit in the mesangium, with subsequent stimulation of complement and immune/inflammatory pathways. Polymeric IgA1 predominantly activates the alternative complement pathway.

Some enzyme deficiencies are hereditary, but these defects alone are not sufficient to give rise to clinical IgA nephropathy. Furthermore, around 20% of patients do not have detectable hypo-glycosylation – so other patho-physiological pathways must also exist.

Wednesday, December 22, 2010

Neutropenia in transplant recipients

* How common is neutropenia after kidney transplantation and when does it usually occur?

About 20-50% of kidney recipients will experience at least one episode of neutropenia. It typically occurs around day 100 after transplantation and it can last from 1-4 weeks.

* What is the etiology of neutropenia in those patients?

The cause is usually multifactorial, but the leading culprit is the use of MMF. Valgancyclovir and bactrim can also contribute directly to neutropenia with their myelotoxicity profile. In one study, tacrolimus was also strongly associated with neutropenia. CNI-induced neutropenia is rare and the most plausible explanation for this association is due to its pharmacokinetic interaction with MMF – FK inhibits MPA glucuronidation, which increases the availability of the active form of MMF. Induction therapy may also contribute to neutropenia, especially antithymocyte antibody (ATG). Interestingly, neutropenia is usually not associated with lymphopenia, anemia or thrombocytopenia. Finally, neutropenia may occur as a consequence of a viral or bacterial infection.

* What is the consequence of neutropenia in transplant patients?

Infections. As in oncological patients, neutrophil count is inversely correlated with frequency and severity of infectious complications. The most common infection is UTI followed by intraabdominal infections.

* How should neutropenia be managed in these patients?

There are no guidelines in transplantation but the most effective way to improve neutropenia is to cut down the MMF dose. Depending on the severity, some patients may even require complete interruption of this drug. The caveat is that longer interruptions (>6 days) have been linked to increase risk of rejection Some centers also stop the bactrim and valgancyclovir. The latter when given at full dose 900mg/day may contribute significantly to neutropenia. In our center for example where ATG induction is commonly used in combination with MMF and FK, the prophylaxis dose of valgancyclovir was adjusted down to a maximum of 450mg/day due to very high incidence of neutropenia with the higher dose.

* If neutropenia does not improve, should we consider G-CSF?

G-CSF has been shown to shorten the duration of neutropenia in cancer patients, but had no effect on the number of culture-positive infections or the rate of hospitalization. In the transplant setting, there has been one report of rejection after G-CSF, but in general is well tolerated. My personal opinion is that G-CSF should be considered a second-line of therapy after adjustment of the other medications.

Prospective trials are needed to validate this approach and careful monitoring for infection/rejection on these patients is essential.

Figure:
Stimulated neutrophil with extracellular traps and some trapped Shigella (orange). Colored scanning electron micrograph. Provided by Max Planck Institute.

Friday, December 17, 2010

Evolution of kidney transplantation in the HIV-positive recipient

The presence of HIV has in the past been viewed as a relative contraindication to transplantation. This stance stemmed from concerns that immunosuppression would exacerbate an already immunocompromised patient and accelerate the disease process of AIDs. Additionally, there was an ethical concern in terms of giving a precious, limited resource to a group with what was in the past considered limited life expectancy.

However, the widespread introduction of HAART in the mid-90s has resulted in a marked decrease in morbidity and mortality in patients with HIV. As a result, people infected with HIV are living longer and dying less often from opportunistic infections and progression to AIDS, and more often from complications of traditional comorbidities such as coronary disease, diabetes, and chronic kidney disease. The incidence of ESRD continues to rise in those infected with HIV, and it is estimated that 1% of patients with ESRD are infected with HIV. In the United States, HIV nephropathy is the third most common cause of ESRD among blacks who are between the ages of 20 and 64.
As a result of this increasing incidence of disease and the improvement in management of HIV, many transplant centers have now eliminated HIV as a contraindication for transplantation. Several small studies have shown promising results, but there is really a lack of quality evidence in this field and it remains a controversial topic amongst nephrologists.

A recent publication in the NEJM has provided some stronger, encouraging data demonstrating that transplanting an HIV-positive recipient is feasible and offers good outcomes.

This study was a multicenter, non-randomized, prospective trial that was conducted at 19 U.S. transplant centers, which was designed to examine the safety and efficacy of kidney transplantation in ESRD patients who were also infected with HIV. The authors followed prospectively 150 HIV-positive recipients for up to 3 years after transplantation. Inclusion criteria were a CD4 count greater than 200 and undetectable viral load in the serum in the 16 weeks prior to transplantation. Patients were excluded if they had a history of PML, CNS lymphoma, or visceral kaposi’s sarcoma. They also were excluded if they did not meet center-specific transplant criteria. Primary outcomes were patient and allograft survival, and secondary outcomes were opportunistic complications, changes in CD4 counts, and detectable plasma HIV RNA levels. Refer to the paper for further details on their methods and post-transplant care.

The authors looked at patient and graft survival rates at years 1 and 3, and compared them to both the survival rates reported by the scientific registry of transplant recipients (SRTR) for all kidney transplant recipients, as well those older than 65. They conclude that patient survival rates in their population were similar to that of the general population, and that allograft survival rates were somewhere between that of the general population and the high risk elderly population. Significant opportunistic infections were minimal and there was no evidence of HIV progression during their follow period. Neoplasm rates were comparable to the general population, and there were no cases of PTLD. Interestingly, as has been previously described, they found their patients to have a very high rate of acute rejection which is much higher than the general population.

While this study does have its limitations, it provides some convincing evidence supporting kidney transplantation in HIV-infected patients. In a carefully selected population of HIV-infected patients with ESRD, it shows that kidney transplantation is a safe and feasible management option.

Justin Westervelt, MD

Thursday, December 16, 2010

Minocycline for the prevention of osmotic demyelination in hyponatremia

There’s a reason that 3 the 10 of the most frequently accessed in “Up to Date” articles relate to the management of hyponatremia. It makes doctors nervous, and I think the main reason for this is the threat of the terrifying osmotic demyelination syndrome (ODS). A murky and poorly understood entity, ODS hangs over every management decision you make and, even if you’ve done all the right things (kept the rate of rise in sodium to less than 8 meq per day, paid attention to the K, given DDAVP and H2O back if necessary) you may still get burned, particularly in alcoholics, cirrhotics and the malnourished. Worst of all, you may not learn your fate until over a week later, when early signs of severe neurological injury start to appear.

During hyponatremia, exchangeable intracellular solutes are redistributed to prevent cerebral edema, leading to gradual loss of intracellular organic osmotically active particles. It can take over 5 days to rebuild these stores. A rapid rise in serum Na forces cerebral vascular endothelial cells to contract, opening the blood-brain barrier and allowing pro-inflammatory cells and cytokines to enter the brain. This causes oligodendrocyte injury, microglial activation and demyelination. An agent that could be given to hyponatremic patients before attempting Na correction, and which prevents this dreaded complication occurring, has enormous appeal. In this month’s JASN, two studies in rats suggest minocycline might be just that.

Minocycline is a tetracycline antibiotic most widely used for the topical treatment of acne. It also appears to prevent spots on the brain, having protective properties in animal models of CNS injury, including demyelination, where it seems work by preventing microglial activation. Both of these JASN studies test its effectiveness, when started several hours before rapid Na correction, in preventing ODS in rats. In the first study, minocycline-treated rats showed less microglial activation, less inflammatory infiltrate and much better survival, although some demyelinating brain lesions did still occur. In the second study, minocycline resulted in a marked reduction in the incidence and severity of neurologic symptoms, although half of the rats died.

These are important studies, not least because they highlight the central role of inflammation and microglial activation in ODS, which I formerly held to be a form of direct osmotic injury. Given that ODS is so rare, it’s going to be quite difficult to study the effectiveness of minocycline in humans. So, don’t be surprised if you start to hear suggestions to give minocycline “just in case” in the ICU. I would resist this for a few reasons. First, I develop a little demyelination of my own (from banging my head against the wall) each time I see a renal patient prescribed N-acetylcysteine -but no iv fluids- pre-contrast. Untested therapies can creep into clinical practice, diverting focus from proven interventions and, once established, are very difficult to expunge. Second, very large doses were used in these animals. We’re a long way from knowing how to dose this in humans. Finally, minocycline frequently causes causes vestibular disturbances (dizziness, ataxia, vertigo and tinnitus), particularly in women (50-70% of the time!). Personally, I can’t think of anything more stressful than being called in the middle of the night because the patient I’m treating with hypertonic saline has just developed nystagmus or ataxic movements. No thanks!

Wednesday, December 15, 2010

Calcineurin inhibitor pharmacokinetics

Here are some interesting points on the pharmacokinetics of immunosuppressant drugs, taken from NephSAP in July 2010. It’s always to good to have an idea of how the body manages these drugs; this can sometimes help to predict potential side effects too.


CYCLOSPORIN:
- Oral absorption is erratic, ranging from 10-70%
- Mean bioavailability is around 30%
- Two-hour value correlates better with AUC than 12-hour trough
- Absorption can be affected by food, fat content of food and GI motility problems. Neoral is a microemulsion that was developed to try to overcome some of these issues – however, there is no proven increase in patient or graft survival
- Has a high volume of distribution (3.5-13L/Kg) and is highly tissue-bound
- Follows zero-order kinetics
- Metabolism is predominantly by the P450 CYP3A4 system; only 1% is excreted unchanged in urine
- CKD and dialysis do not affect metabolism
- To convert oral to intravenous, the conversion should be approximately one third of the daily oral dose and should not exceed 2mg/Kg/day

TACROLIMUS:
- Mean bioavailability is 20-25%
- It is highly protein bound, having a higher concentration in whole blood than plasma; therefore levels should preferably be monitored in whole blood
- Metabolized predominantly by CYP3A4 in the liver
- To convert oral to intravenous, the conversion should be approximately 15-20% of the daily oral dose
- Seems to cause less hypertension and less dyslipidaemia (but more diabetes) than Cyclosporin

Tuesday, December 14, 2010

PD: Catheter outflow failure

I recently saw a patient in our peritoneal dialysis clinic who had been ultrafiltering about a liter a day but who was now consistently draining 100ml less than his instilled PD solution volumes despite extended drain times and multiple acrobatic contortions to try and recover additional fluid.

Peritoneal catheter outflow problems are common and many PD patients transfer to hemodialysis because of catheter related issues. Peritoneal outflow failure can be defined as the incomplete recover of instilled dialysate consistently within 45 minutes of beginning a drain.

So what are some of the things you can do when faced with a PD patient who is having difficulty recovering their dwells? Recently, an article in AJKD reviewed the topic and the salient points are outlined below.

1) Check for peritonitis – Start by looking for signs and symptoms then look at the dialysate to see if it’s overtly cloudy followed by a dialysate cell count and culture. During episodes of peritonitis the permeability of the peritoneal membrane to water, glucose and proteins is increased. This leads to rapid loss of the osmotic gradient as glucose moves from the dialysate into the blood resulting in reabsorption of fluid if dwell times are long enough.

2) Check a KUB – Useful for many reasons. The KUB can help you see catheter kinking, tip migration and constipation, which is very common culprit of outflow obstruction.

3) Examine the patient for signs of catheter leakage – Pericatheter leaks usually show up soon after catheter placement as wetness on the exit site dressing. Leakage of dialysate can also occur at any time into the abdominal wall, the pleural space (usually the right) and the genitals.

4) Is there resistance to dialysate or saline instillation? – If it’s tough getting fluid in in addition to getting fluid out something inside or outside the catheter is blocking it up. Inside kinks (which you might have seen on the KUB), fibrin and blood clots are potential culprits. Outside dilated stool filled intestine, and other intrabdominal organs in particular the omentum may be occluding the catheter. If fluid flows freely in, and the above options have been ruled out ultrafiltration failure should be considered.

In our patient, exam was unremarkable apart from trace lower extremity edema and saline was easily instilled into the peritoneal dialysis catheter by one of our RNs. The recovered PD dialysate was clear and cell count was zero. A KUB showed stable catheter position without kinking and copious stool. We started a trial of laxatives and were gratified to hear a few days later that our patient was now achieving his former ultrafiltration volumes.

Sunday, December 12, 2010

An eye opener!

Call it serendipity or mere coincidence, I recently saw a patient with Prostate cancer treated with an experimental chemotherapy protocol that was sent to our clinic for evaluation of Fanconi syndrome and proteinuric stage 3 chronic kidney disease (1.5 g/d).I did a kidney biopsy which revealed extensive proximal tubulopathy with moderate interstitial fibrosis but no glomerular disease was noted. Interestingly, serum and urine protein electrophoresis with immunofixation was negative. Work up to find the underlying etiology of Fanconi syndrome was an exercise in vain. The etiology remained a puzzle until a case presented at ASN in Denver was an eye opener for me. This case introduced to me the possibility of Isolated Light chain proximal tubulopathy (LCPT) as a cause of Fanconi syndrome in my patient despite a negative serum and urine protein electrophoresis.

Briefly, plasma cell dyscrasias are characterized by excessive bone marrow production of immunoglobulin freely circulating in the plasma. Several pathologies are noted in the kidney and include:

1) Light chain (myeloma) cast nephropathy.
2) Monoclonal Immunoglobulin deposition disease
3) Amyloidosis
4) Tubulointerstitial nephritis
5) Cryoglobulenemia

Rarely, LCPT has been reported and often precedes the diagnosis of multiple myeloma, MGUS, and less commonly amyloidosis.Light chains, almost always, are kappa chains.
In a normal state, the light chains that cross the glomerular filtration barrier are endocytosed through glycoprotein receptors megalin/cubilin in the proximal tubule and are subsequently degraded by the lysosomal proteolytic enzymes into several amino acids. However, in patients with LCPT, the variable segment (VK1) of the kappa light chains is resistant to degradation by the lysosomal proteolytic enzymes and binds other fragments of light chains to form crystals that get deposited in the proximal tubular epithelium and cause disease. Clinical presentation is very varied and often includes renal dysfunction with fanconi syndrome, although these findings are not universal.

Histologically, on light microscopy (high power), pale, rhomboid intracytoplasmic crystals are seen in the proximal tubular epithelium. Immunofluorescence (IF) often stains positive for kappa light chains and electron microscopy is confirmatory for the pale crystalline structures in the proximal tubule epithelium.

However, the diagnosis of this condition may be difficult due to several reasons:
1) Clinical presentation is often heterogeneous and fanconi syndrome is not a universal presentation.
2) Detection of intracytoplasmic crystals in proximal tubule can often be missed without heightened suspicion.
3) SPEP with immunofixation can be negative and UPEP with immunofixation may be a less sensitive study (read this blog).
4) Standard IF staining for kappa light chain can be negative as antiserum may not always bind partially degraded kappa light chains.

It is therefore recommended that free light chain assays be performed along with IF following pronase-digestion (details here) or immunoelectron microscopy in cases where the diagnosis is not clear. Once the diagnosis of LCPT is made, extensive work up including skeletal survey and bone marrow biopsy is recommended to rule out plasma cell dyscrasias.

With this enlightenment, I called my pathologist, who reminded me that IF could not be done on my patient due to only one core of tissue, but she did promise to send the paraffin embedded section for IF. I have also asked my patient to get the free light chain assay.

Viresh Mohanlal, MD

Friday, December 10, 2010

Bardoxolone for diabetic CKD preliminary results presented at ASN

Preliminary results from a phase IIb clinical trial funded by Reata Pharmaceuticals and Abbott were presented at ASN Renal Week 2010 in Denver, CO last month.  This study looked at the novel drug bardoxolone (RTA 420) in diabetic CKD.

Bardoxolone is a first-in-class drug touted as an antioxidant inflammatory modulator (AIM).  It is a potent inducer of the Nrf2 pathway.  Nuclear factor-erythroid-related factor 2 (Nrf2) plays a critical part in basal activity and coordinated induction of genes encoding numerous antioxidant and phase II detoxifying enzymes (including catalase, superoxide dismutase, glutathionse s-transferase etc.).  Nrf2 is ubiquitously expressed, but is dispensable for normal development.  Nrf2 KO mice have decreased phase II detoxifying enzymes and endogenous antioxidants.  Nrf2 was originally identified for its anti-cancer properties and substantial efforts are underway to develop Nrf2 inducers in a variety of malignancies.  Reactive oxygen species generation (oxidative stress) has been linked to the pathogenesis of many human diseases other than cancer. There has been accumulating evidence of a protective role for Nrf2 many diseases such as Alzheimer's, Parkinson's, ischemia, aging, diabetes, cardiovascular disease, autoimmune disease and kidney disease.  For a review click here.

This is an ongoing multicenter, randomized, double-blind trial funded by Reata and Abbott.  The results are reported at 24 weeks of a planned 52 week study (which the investigators state they will begin to analyze in January 2011). 227 patients with CKD (eGFR 20-45) with type 2 diabetes were randomized to receive once-daily doses of placebo or 25, 75 or 150 mg doses of bardoxolone.  Mean age- 67, mean diabetes duration- 18 yrs, average A1c- 7.2, mean BP 130/69, 75% were obese, baseline eGFR average- 32, all were on either ACEi or ARB. The primary endpoint was change in eGFR following 24 weeks of treatment.

At week 24, patients treated with bardoxolone had a mean increase in estimated GFR of over 10, compared with no change in the placebo group. Approximately three-fourths of bardoxolone treated patients experienced an improvement in eGFR of 10% or more, including one-fourth who saw an improvement of 50% or more compared to less than 2% of patients on placebo (P=0.001). Adverse events were higher in the bardoxolone group. The most frequently reported adverse events were muscle spasm (49% vs 12%), nausea (19% vs. 4%, hypomagnesemia (18% vs 4%), decreased appetite (15% vs 2%).

What do we make of these results?  First- this is just preliminary results (24 out of 52 weeks) of a phase IIb clinical trial.  Results of another phase II clinical trial were presented in 2009 at the American Diabetes Association showed significant reductions in creatinine, BUN, uric acid, A1c and phosphorus in the treatment group. It was refreshing to see several positive studies presented at Renal Week this year.  However, we will have to wait for the 52 week results and a larger Phase III clinical trial which is expected to start at the end of this year to make any definitive  conclusions.  Secondly, the rate of adverse events will need to be addressed as 49% experiencing muscle spasms seems quite high. On a side note- it is well known that ACEi and ARBs cause an initial decrease in eGFR, however in the long term they delay the progression of CKD.  So, it will be interesting to see if this increase in eGFR by bardoxolone holds up over time.  We will see where this story goes. 

Thursday, December 9, 2010

Drug-induced hyponatremia

When reviewing a consult patient with hyponatremia, the first thing I look at is the medication list to see if the culprit is to be found there. Along with the usual suspects - diuretics, NSAIDs, SSRIs and anti-convulsants, there are a number of other medications that need to be considered. Very helpfully, this review in AJKD lists most of the causes of drug-induced hyponatremia and provides the rationale for why hyponatremia occurs in the setting of these drugs.

There are a number of broad categories into which most of these medications fall:
1. Drugs which affect sodium and water homeostasis: Thiazide, loop and k-sparing diuretics all fall into this category although it also includes co-trimoxazole, because of the diuretic-like effect of trimethoprim on the distal tubule.   

2. Drugs which increase ADH secretion from the pituitary: These are primarily psychotropic drugs e.g SSRIs and antipsychotics. It is important to distinguish SIADH from psychogenic polydypsia in these patients and to recognize that they may exist concomitantly. Other medications that can increase ADH secretion include anti-epileptics (e.g. carbamazepine), opiates and some anti-cancer agents.  

3. Drugs which increase the sensitivity of the distal tubule to ADH: Carbamazepine again, cyclophosphamide and NSAIDs.  

4. Drugs which reset the osmostat: Venlafaxine and (yet again) carbamazepine.  

5. Drugs which cause pseudohyponatremia: IVIg and mannitol.
    There are a number of other drugs which do not fit neatly into any of these categories which include MDMA, some antibiotics and, interestingly, PPIs. However, most of these (apart from MDMA) have only been seen in isolated cases and should really only be considered if there is no other apparent culprit for the hyponatremia.

    This is a helpful way to think about drug-induced hyponatremia and is useful in determining the best way to manage low sodium in these patients (after stopping the offending drug, of course).

    Wednesday, December 8, 2010

    Lupus - persistent low complements

    Consider a patient with long-standing SLE who has biopsy proven WHO class IV lupus nephritis, previously treated with cyclophosphamide and steroids, which induced remission. Due to recurrence of proteinuria and desire to remain steroid-free, MMF was commenced with good effect. Other maintenance treatment from our Rheumatology colleagues included hydroxychloroquine for extra-renal manifestations of lupus.

    A subset of patients, despite having minimal proteinuria, no haematuria and no flares requiring steroid treatment, have persistent hypocomplementaemia. This got me thinking that these patients may possibly have persistent sub-clinical activity – the question being, what do we do – treat the numbers or treat the patient?

    A retrospective review was recently published looking at a similar patient group. Examination of over 28 years of data identified 56/924 patients who had clinically quiescent disease for two years, during which they had no steroid or immunosuppressant treatment (other than anti-malarials) but had persistently elevated anti-dsDNA and/or hypocomplementaemia. These patients had a lower baseline disease activity score and a lower need for steroids or immunosuppression use up front than those not meeting these criteria.

    In this ‘clinically quiescent serologically active’ group 62.5% had both elevated anti-dsDNA and hypocomplementaemia, 23.2% had elevated anti-dsDNA only, while 14.3% had hypocomplementaemia only. During follow-up, 58.9% developed a flare at a median of 155 weeks, 10.7% developed normal anti-dsDNA and complement levels (clinically quiescent serologically quiescent) and 30.4% had persistent elevations in anti-dsDNA and complement levels (remained clinically quiescent serologically active).

    To compare those who flared with the other two groups, they reviewed levels of anti-dsDNA and complement levels from their previous visits prior to the flare. They found that absolute levels or change in levels of anti-dsDNA or complements did not predict flares.
    Also of note, in comparing the original 56 patients with the remainder of the group there was no statistically significant difference in mortality during follow-up between the two groups (14.2% v 5.4% p=0.06).

    The authors’ conclusions were that the clinically quiescent serologically active subgroup certainly warrant close monitoring (as 59% ultimately develop a lupus flare), but that treatment should be based on clinical findings, not the numbers.

    Friday, December 3, 2010

    High Maintenance

    Many nephrologists will have faced “interesting specialty, shame about the evidence-base” jokes in the past. However, following a profusion of randomised controlled trials in lupus nephritis, we are now entering an era where we can integrate data to make truly evidence-based treatment plans.

    The latest randomised trial to appear is the MAINTAIN study. This was designed to assess whether MMF is superior to azathioprine (aza) in the maintenance phase of treatment of biopsy-proven proliferative lupus nephritis. For the most part, recent studies in lupus have focused on induction treatment, with an emerging consensus that MMF and IV cyclophosphamide (IVC) are at least equivalently efficacious with a favourable avoidance of ovarian failure associated with MMF.

    MAINTAIN was an open label study of 105 patients who were followed-up for 48 months. All patients received induction treatment with steroids and IVC before being randomised to either MMF or aza regardless of renal response to induction. The primary endpoint was time to renal flare (defined as either development of nephritic syndrome, a 33% climb in serum creatinine or 3 fold increases in urinary protein); secondary end points were set as the numbers of severe systemic and benign flares, those withdrawing steroids and those achieving renal remission.

    The headline result was that whilst fewer renal flares (25% v 19%) were seen in those treated with MMF this, and all secondary end points, did not differ significantly.

    So what is important and original about MAINTAIN? Well, recent publication of the 10 year results of EUROLUPUS has shown the effectiveness of aza as a maintenance therapy. Therefore, given that MMF is about 15 times more expensive than aza and carries a reasonable burden of side effects, some feel it should be demonstrated to be superior to justify its widespread usage.

    The trial was performed in Europe with a huge Caucasian predominance. This is likely to be relevant given the racial disparity in MMF response demonstrated during the induction phase of the ALMS trial. ALMS was designed to compare MMF and IVC as induction therapy for 24 weeks and then saw re-randomisation of patients to MMF and aza. Black and Hispanic patients responded better to MMF. The maintenance phase results of ALMS are now available in abstract form and show that MMF was superior to aza in preventing a composite end point of death, renal damage, and renal relapse. This difference between MAINTAIN and ALMS may be a result of the fact that in ALMS only patients who had achieved a renal response at 6 months were included in the maintenance phase, or because a composite end point was used in ALMS, or, more simply, because ALMS was larger (227 randomised patients v 105 in MAINTAIN).

    So what more do we need for trial evidence in lupus? Some long term data focused on ESRD and death would be helpful. Especially if it focused on those patients both induced and maintained with MMF. One thing is for sure though, the days of expert opinion guiding treatment of glomerular diseases is receding fast.

    Tom Oates M.D.

    Thursday, December 2, 2010

    Pseudohyperkalaemia with extreme leucocytosis

    We were following a CKD patient with CLL in hospital with the haematology team. One morning, out of the blue, his potassium came back at 6.5mmol/L. It had been stable in the high four range for the duration of his admission to that point. There were no changes to his diet or medications – nothing to blame that we could ascertain.

    When the team called us, we suggested repeating the lab draw stat, taking care to minimize any chance of haemolysis (avoid tourniquet etc.), and to perform an ECG while we were waiting for the repeat result to come through. The ECG showed normal sinus rhythm and no changes associated with hyperkalaemia; the patient looked well, but the repeat serum sample came back at 6.7mmol/L!!!
    Very importantly, looking through the rest of his lab results we noted his peripheral white cell count was shooting up (>100K). A spark of inspiration from one of the attendings wondered if this could be pseudohyperkalaemia from extreme leucocytosis?

    Potential mechanisms for pseudohyperkalaemia in cases of leucocytosis and thrombocytosis include:
    1. release of K during the clotting process of collected blood 
    2. abnormally high fragility of the leucocytes. 
    Other factors that increase tendency for lysis include increased temperature, length of sample standing time, use of pneumatic blood drawing devices, tourniquets and ‘difficult sticks’. Due to the influence of the clotting process, plasma samples more closely reflect the true potassium level than serum samples in these patients.

    If a case of pseudohyperkalamia is suspected, then it’s important to figure out what type of tube the blood is collected in at your hospital. Simultaneous samples should be taken for plasma and serum processing. If pseduohyperkalemia is present, the plasma sample will be the more accurate – we sent a sample in arterial blood gas syringe (which are heparinized, processed very quickly and the results based on plasma samples) – the K came back at 4.8mmol/L, avoiding unnecessary and potentially dangerous treatment.

    A final point in ensuring patient safety in this scenario is accurate handover to night-staff or change of shifts – make sure everyone knows to order and treat according to the plasma sample.

    See Nate's post for other causes of pseudohyperkalaemia or Justin's post on a similar patient presentation.

    Wednesday, December 1, 2010

    Should you stop ACE inhibitors prior to major surgery for renoprotection?

    I must admit that I have always routinely advised holding ACE/ARB prior to major surgery, given the possibility of hemodynamic instability and assumed risk of AKI due to impaired renal autoregulation when perfusion pressure is low. I’m prepared to accept that I might be biased, as so much of the AKI I see relates to ACEi use, especially in the elderly. But, as it turns out, the question of continuing ACEi pre-operatively is surprisingly controversial. It seems cardiac surgeons are completely split down the middle on the question. Of 167 practicing UK cardiac surgeons who were asked “Do you think it’s beneficial to stop ACEi pre-surgery?” 40% said yes, 40% said no and 20% just grunted. Some even advocate their use for the prevention of AKI. So, you may yet have a friendly tete a tete with your local cardiac surgeon over this issue, and a brief recap of the evidence may stand to you in such an event.
    What is immediately striking when you begin read around this issue is the existence of 2 pitched positions, similar to the ongoing debate on renal artery stenting. On the one hand Nephrology journals mostly carry studies supporting ACE avoidance, whereas Anesthetic/Cardiothoracic Surgical journals only seem to have trials that support of ACE continuation. This observation is of itself unsettling, as it suggests to me the existence of publication bias.
    Evidence for continuing ACEi:
    1. Although small (N=14 CABG patients), this prospective study of 48 hours of iv enalaprilat vs placebo showed that cardiac index, SVR, renal plasma flow (measured by hippurate) and creatinine clearance (measured by timed urine collection) were all significantly improved in the treatment arm and the effects lasted up to post-operative day 7.
    2. This small placebo-controlled double blind trial (enalapril vs. placebo) of 40 patients with LVEF < 35% undergoing CABG also showed improved GFR in the treatment arm (GFR increased from 66 to 80; p=0.009 vs no change in placebo).
    3. Finally, a prospective multivariate analysis of 536 patients undergoing on-pump CABG, where AKI was defined as a 50% decrease in GFR. The authors observed a reduced rate of AKI associated with pre-op ACEi use (ACE OR 0.48 0.23‐0.77 p = 0.04). The authors tried to reduce selection bias through the use of propensity scores – adjusting for likely group membership (i.e. ACE vs. no ACE) – which are controversial.
    Evidence against continuing ACEi:
    1. A larger study by Arora et al. (1358, mostly CABG patients), but retrospective and, again, employing propensity scoring to try and mitigate selection bias. Nonetheless, they did observe a 40% increased risk of AKI in multivariate regression analyses.
    So where does this leave us? Two small, randomized, prospective studies show a benefit in hemodynamic parameters and GFR. These are consistent with the known vasodilatory effects of ACEi on the systemic and renal circulation, and I have no trouble believing them. However, they do not address the issue of response to a hypotensive insult while on an ACE, which is the crux of the problem in my opinion. Then, we have conflicting evidence from 2 larger observational studies, both of which are concerning for selection bias, with one suggesting the possibility of harm. Based on the above, I would agree with Thomas Berl’s assessment at this years ASN, and invoke Pohl’s rule: “Never trade an unknown benefit for a potential complication.” Given there is no convincing renal benefit to continuing ACE/ARB prior to surgery, and the real possibility of harm, I would hold these drugs for surgeries where post-op hemodynamic instability is likely.