Rapamycin and PCKD

A couple of years ago, it was noted that mTOR inhibitors slowed the growth of cysts in animal models of Polycystic Kidney Disease. Although the activity of mTOR is minimal in normal renal epithelial cells, in cyst epithelial cells, expression is markedly increased. At the time, there was understandably a lot of excitement about this and the potential for a role for rapamycin for treating patients with PCKD. (We got in on this ourselves and had two posts from Nate and Conall about this possible therapeutic pathway) Unfortunately, the clinical studies were not very impressive and the excitement has since faded somewhat. One of the reasons put forward for why it was ineffective was that the doses were inadequate. The dose of rapamycin needed to suppress cyst growth in mice was far higher than was tolerable for humans. Anyone who has used rapamycin in transplant recipients knows about the side-effect profile which prevents many people from taking the drug,

An article was just published in JASN which raises the possibility that rapamycin could be used in higher doses than previously thought possible. The folate receptor is selectively expressed on cancer cells and renal epithelial cells. As a result, there has been some work done on combining drugs with folate to increase the specificity of drug delivery, particularly chemotherapeutic agents and thus limiting toxicity. The beauty of this is that folic acid is taken up into most cells by an alternative pathway and this pathway is not available to conjugated folate. In this study, the authors conjugated rapamycin to folate and gave it to mice with PKD. They showed that it was effective both at reducing expression of downstream targets of mTOR and slowing cyst growth. This suggests that the combined compound could be given in large doses to humans with PKD and offer targeted therapy with less chance of significant extra-renal side effects.

Photo from the University of Indiana website

Bardoxolone - Part 3

Last year, we had a post about Bardoxolone for the treatment of diabetic nephropathy. After one year of treatment, eGFR increased significantly in patients treated with Bardoxolone relative to controls. At the time, significant concerns were raised about the fact that albuminuria also increased in patients receiving the drug and it was uncertain both what the mechanism of this was and whether there would be any deleterious consequences. 

This week, an article was published in JASN which goes some way towards explaining the reason for the proteinuria. Under normal circumstances, a significant quantity of albumin is filtered in the glomerulus. Almost all of this albumin is reabsorbed in the proximal tubule by the cubilin-megalin complex. Defects in cubilin and megalin have been associated with albuminuria in animals and humans. It turns out that Bardoxolone downregulates the expression of megalin in monkeys in the proximal tubule. Thus, the increase in albuminuria may be due to decreased effectiveness of the retrieval process. At one year, there were no significant differences in renal histology between the treated monkeys and controls. 

This is a fascinating finding. There has been a lot of work done in the last few years regarding the effect of albuminuria itself on renal fibrosis. Even in the absence of any vascular changes, overload albuminuria is associated with increased fibrosis in animal models. So, why is there no damage seen in these monkeys? One of the postulated mechanisms of albuminuria-induced fibrosis is that megalin itself acts as a transmembrane receptor and stimulates EGF production in the presence of excess tubular albumin. This ultimately leads to increased interstitial fibrosis. The loss of megalin in treated monkeys means that this pathway might be downregulated. It should be said that these were healthy monkeys and the effect in humans with more albuminuria at baseline could be different. That said, this study goes some way towards alleviating some of the concerns that were raised last year.

The Good the Bad and the Ugly - Uric Acid and the Kidney

At some point during evolution humans lost the enzyme uricase and during the long and tedious process of getting to the modern age and this was initially a good thing. Uric acid accumulation as a result of uricase loss is thought to have been protective in situations of hypotension in low salt environments, conferred increased intelligence and reduced oxidant stress (although some authors consider this highly speculative). The Nephrologist often has a role in managing gout, since uric acid is mainly excreted by the kidney.

So now that we do not have a shortage of salt anymore and our diet is rich in purines we get to see the drawbacks of evolution. This comes in the unpleasant form of gout. Most of the time, gout is caused by under-excretion of uric acid by the kidney and only in the minority of cases (~10%) by overproduction. Renal uric acid handling is complicated and about a decade ago a transporter with specific apical urate-anion exchange activity was described.

Gout can be triggered by a number of gluttonous habits:

• Alcohol - causes increased urate synthesis and increased lactate production which increases urate reabsorption
• Foods high in purines increase uric acid levels.
• Lead causes increased uric acid levels by impairing urate excretion, which is associated with the development of gout (termed “saturnine gout”). This was much more common in older days when lead ingestion was high.
• Dietary fructose acutely raises serum uric acid levels.

Therefore gout was considered a "true nobleman's disease" in earlier centuries and artists such as William Hogart used to portray them in their works.

Now some people are worse off because they have to take medications that cause hyperuricemia. Amongst them are transplant patients depending on immunosuppressants and diuretics, for example a heart transplant patient whom I recently saw in clinic.

Cyclosporine: Decreased GFR and possibly tubular damage contribute to cyclosporine induced uric acid retention. Tacrolimus does not offer any advantage over cyclosporine. A study in children with transplants concluded that cyclosporine induced tubular reabsorption of uric acid.

Diuretics:HCTZ is a common trigger of gout attacks but all other diuretics also do. Rising serum uric acid with diuretic use occurs with low doses and increases dose-dependently. Volume depletion stimulates a marked increase in proximal tubular reabsorption of urate. The mechanisms involved in the regulation of urate reabsorption by extracellular volume status are however unclear. Furosemide can induce hyperlacticacidemia sufficient to suppress tubular excretion of urate. Diuretics have also been shown to interfere directly with uric acid handling by the kidney. Loop diuretics and thiazides have been shown to directly inhibit NPT4-mediated urate secretion and furosemide can inhibit urate uptake by URAT1.

Management is aimed at lowering serum uric acid levels with Allopurinol or Febuxostat. Febuxostat is an alternative to allopurinol in patients with allopurinol intolerance or hypersensitivity.  In my (limited) experience uricosuric drugs such as Probenecid are rarely used in practice anymore and the teaching is that they actually can trigger acute gout attacks by initially decreasing excretion. Pegloticase, a pegylated recombinant porcine-like uricase, can be given in severe cases when Allopurinol or Febuxostat are not effective. The drug needs to be given IV but thanks to its long half-life only every 2-4 weeks.

Posted by Florian Toegel

Career Choice for Nephrology Fellows

This month's eJournal Club article is not a traditional, clinical or basic research article but instead one which looks into the state of nephrology training in the US. There has been a significant decline in the number of residents applying for nephrology fellowships over the last 10 years and this has naturally caused some concern for the powers that be. More than half of nephrology trainees are now foreign medical graduates (including yours truly) and a committee has been set up by the ASN to explore means of increasing interest in nephrology careers among trainees and medical students. This article reports the results of a survey of nephrology fellows that was completed over the last 2 years.

The article highlights the importance of early mentoring in the decision to pursue a nephrology career. The second most important factor was interest in nephrology as a subject. I sometimes feel that the way that nephrology is presented to students means that they feel that it is too complicated and difficult and it puts them off. It is important for us to highlight the diversity of opportunities that are available in nephrology.

One good thing to mention is that most fellows who were surveyed were happy with their career choice. Only 7.5% of people for whom nephrology was their first choice regretted their decision. The number was higher for those for whom it was a second choice. Hopefully, the results of this survey will be utilized to try and identify areas to focus on to increase interest in nephrology again. We have a great specialty and we should let people know!

The discussion continues at CJASN. 

One flew over

When I got my US driving license, I was asked whether or not I would like to be an organ donor. To me, having seen the positive effects of donation on the lives of my patients down through the years, the obvious answer was yes. However, it is good to be reminded every now and then how difficult it can be for families to agree to donation.

Letters of Note is a blog that collects letters from around the world and throughout history on all kinds of topics. Today's letter is from Ken Kesey, the author of "One flew over the cuckoo's nest", which he wrote to his friends following the death of his son in a bus accident in 1984. He describes the process of deciding to donate his son's organs and how the whole family was there to say goodbye. For this family, at least, it was a positive experience that gave some meaning to the tragedy.

It reminds me that, although we should always encourage people to donate, we should never take it for granted when they do, and we should never look badly those who feel, for any reason, that they cannot.

Stress test for renal transplant candidates: select or screen all?

We have previously discussed cardiovascular mortality after transplantation. But one controversial aspect in the evaluation of potential kidney recipients is the performance of stress tests for risk stratification. With the cost of stress tests ranging from U$2,500-5,000 and the long waiting time for a kidney transplant on the deceased donor list, this is a particular important point for financial, medical and logistical reasons. 

To evaluate that, De Lima et al. studied the prognostic value of myocardial scintigraphy in 892 consecutive renal transplant candidates classified into four risk groups: very high (aged ≥50 years, diabetes and CV disease), high (two factors), intermediate (one factor) and low (no factor). After a median follow up of 22 months, 181 major CV events were observed (overall incidence = 20%): 12 (6.6%) in low-risk, 51 (28.2%) in intermediate-risk, 61 (33.7%) in high-risk and 57 (31.5%) in very high-risk patients (p below 0.0001; Figure below). This simple classification was able to nicely separate the different groups according to incidence of major CV events.

The prevalence of abnormal scan increased with the degree of risk, from 12.7% in low-risk patients to 50.8% among very high-risk subjects. Interestingly, only in patients with one risk factor (either age ≥50 years, diabetes or CV disease) was an altered myocardial stress test associated with an increased incidence of major CV events [30.3 versus 10%, hazard ratio (HR) = 2.37; p below 0.0001). Low-risk patients did well regardless of stress test results, while in patients with 2 or 3 risk factors, altered stress test did not add to the already increased risk for future CV events. 

The question that remains is whether an invasive intervention could lower the CV events in the high-risk groups and if coronary angiography should be considered instead of stress test, as proposed by some. The cost, invasiveness and risk of the procedure would likely be unwarranted until a randomized trial show benefits of revascularization in ESRD pts compared to medical management. It is important to remember that most clinical trials addressing this question excludes ESRD patients so we must extrapolate data from the general population, which do not support intervention in asymptomatic patients. An upcoming randomized controlled trial is addressing this question in transplantation: COST trial.

Until then, we have to base our decisions on observational/restrospective data and poor evidence-based guidelines. My personal approach has been not to screen low risk patients with stress test anymore but I am still performing stress tests for the intermediate and high risk patients. The reason to do a stress test on a high risk patient is not to assess for the presence or not of CV disease, but to attempt to identify a large defect, exercise-induced hypotension or angina that might warrant intervention prior to transplantation. Among the stress tests, I usually recommend a MIBI protocol with sequential exercise followed by pharmacological (if HR goal not achieved), which allows for evaluation of patient's exercise capacity and cardiac imaging to determine the burden of CV disease. For obese patients, PET may give you better images. 

To provoke even more the debate, Diamond et al. supports the approach of: "test no one and treat  everyone" for asymptomatic diabetic patients compared to "screen everyone and treat only those with an abnormal test". The authors believe that optimal medical interventions such as statins/beta blocker are sometimes ignored after a normal stress test (high false negative rate), missing an important point of intervention, which could be more cost-effective than the screening strategy. Definitely lots of fuel for more debate...

  

Medication Nonadherence in Renal Transplantation: Barriers and Consequences

It is surprising how high the nonadherence rates for immunosuppressants is among renal transplant recipients, ranging from 15 to 40%, despite the potential impact of nonadherence and the degree of education provided to transplant recipients.

Nonadherence to immunosuppressive medications is associated with increased incidences of allograft rejection and a seven-fold increased risk of graft failure as compared to adherent patients. Approximately 20-25% of nonadherent renal transplant recipients develop a late rejection at five years posttransplant, frequently antibody-mediated, as compared to 5-8% of adherent patients. Even a short period of nonadherence to immunosuppressive medications can initiate the rejection process.

Identifying possible barriers to adherence and intervening accordingly is necessary for improving transplant outcomes. One of the well-studied barriers is the complexity of the immunosuppressive regimen. Choosing a simpler regimen among possible effective regimens is likely to provide convenience to patients and; therefore, improve adherence. In addition, forgetfulness is one of the most common causes of missed doses. Nonadherence is more prevalent in patients with comorbidities that can cause impaired cognitive function. 

Some interventions to improve adherence include: associating medication administration times with a daily activity (such as meals, waking up, or going to bed), using pill boxes, and setting alarms or voice reminders that help patients remember to take their medications at the right times.

Ineffective communication may also increase the probability of intentional nonadherence due to a poor understanding of the benefits and risks associated with the patients’ prescribed medications. Most medications used in the transplant setting are preventive, and patients do not perceive the benefits of the medications immediately, which may facilitate nonadherence. Although fear of developing side effects can complicate patients’ nonadherence, patients are more likely to be adherent to a medication when they are aware of its possible adverse effects, which highlights the importance of educating patients. High drug costs can limit patients’ access to medications and increase nonadherence rates. Even with Medicare part B coverage, there are significant copays for patients without secondary insurance. Also, even if patients have prescription drug coverage, the high number of medications needed for some transplant patients can result in high monthly out-of-pocket expenses. This ongoing financial burden is substantial for most patients, and could act as a barrier to adherence when it is not addressed and adjusted. 

It is imperative for renal transplant recipients to adhere to medication regimens, as it can directly affect outcomes. Clinicians should assess adherence at every follow-up and keep in mind possible barriers to medication adherence, in particular, complexity of regimen, financial burden and lack of knowledge of potential consequences of nonadherence.

Miae Kim, PharmD, PGY2 Resident in Transplant Pharmacy

Steven Gabardi PharmD, FCCP, BCPS, Organ Transplant Clinical Specialist at BWH

A Quest for a Pot of Gold

In the quest for better solute clearance, two divergent paths were taken on each side of the Atlantic. The US nephrology community has concentrated more on low weight molecules. The European counterpart has focused on both low and middle weight molecules.

The European endeavor has led to the evolution of the on-line hemodiafiltration (HDF), combining HF and HD. A water-permeable filter allows middle molecule removal by convection. Dialysate then supplements low molecular weight solute removal by diffusion. Production of the replacement fluid from dialysate in the circuit (thus called “on-line”) cuts the cost.

Since Fresenius’ Online Plus™ came out in 1998, on-line HDF has gained popularity in Europe and other continents. In the US? Not so much, but we may see it more as it was just cleared by FDA for the market this April.

The idea of middle molecule removal sounds physiological. But is there really any advantage?

It has been suggested that the on-line HDF may reduce intra-dialytic hypotension, improve nutritional status, and decrease ESA (erythropoiesis stimulating agent) requirement. But what about the hard end points (all-cause mortality and cardiovascular outcomes)?

In the recent CONTRAST study, 700 patients in the Netherlands, Canada, and Norway were randomized to on-line HDF or low-flux HD. The surprise? There was no CONTRAST between the two groups… The CONSOLATION was a minimal survival benefit among those who received top-quartile convective volume.

Did this disappoint the nephrology community? Yes, to some extent. In a recent CJASN editorial, Dr. Kuhlman from Germany pointed out  that in Europe the advantages of on-line HDF over conventional HD have been “somehow taken for granted”.

Did this put an end to on-line HDF? The answer is no. A couple of more European studies are on their way, so is the research to solve technical challenges. This is a never ending journey, even if it may end up with the quest for a pot of gold at the end of the rainbow.

Posted by Tomoki Tsukahara

From acid to nephrocalcinosis to stones

Can you have an acidosis with normal serum bicarbonate? Of course you can, it's just incomplete. Incomplete distal renal tubular acidosis (idRTA) that is.

RTA was first described in 1935, confirmed as a renal tubular disorder in 1946, and designated “renal tubular acidosis” in 1951 (see here for an excellent review). Now it gets complicated, not only with regard to nomenclature but also with mechanisms.

I was a little surprised to hear that you can have distal RTA with a normal bicarbonate. It is just disguised. Patients with incomplete distal RTA have persistently high urine pH but are still able to excrete acid under normal conditions (therefore the normal serum bicarbonate). However, in states of high acid loads (high protein diet, catabolic stress) they are unable to excrete that acid which then triggers alkali release from the bone and thus causes greater bone resorption, therefore these patients have frequently osteopenia and osteoporosis.

Distal RTA occurs with a number of conditions, amongst them classically Sjogrens syndrome but also other autoimmune conditions. Cisplatin has been mentioned as one of the causes of idRTA in this blog earlier. idRTA is a common cause of nephrocalcinosis - with or without stones - and it has a number of prominent victims as also mentioned in a previous post.

idRTA can be diagnosed by induction of a systemic metabolic acidosis by means of acid loading. This is  commonly done with ammonium chloride (NH4Cl) but there is also a furosemide and fludrocortisone test that apparently causes less abdominal discomfort. Failure to acidify urine to a pH of less than 5.3 is consistent with incomplete distal renal tubular acidosis. However, testing is a little bit tedious and therefore not commonly done. The urinary citrate is commonly low in dRTA which contributes to nephrocalcinosis and stone formation.

A recent study from Switzerland showed that 6.7% of 150 male recurrent calcium stone formers (RCSFs) had idRTA, i.e., 1 out of 15 male RCSFs can be expected to have idRTA. They therefore suggest that idRTA is overall underdiagnosed.

Posted by Florian Toegel