Aristolochic Acid Nephropathy

Aristolochic acids (AA) are found in products derived from the aristolochia genus of plants which are used extensively in herbal medicines, particularly in Asia. Nephrotoxicity resulting from AA exposure was originally described in a case series of women taking diet supplements in Belgium but has subsequently been identified in the US, Europe and Asia. Consumption of products containing AA remains endemic in some areas with an estimated exposure in up to 40% of the Taiwanese population. The disease known as Balkan endemic nephropathy – described the population living around tributaries of the Danube river- is now thought to result from contamination of wheat flour with seeds of plants containing AA.

Patients with AA nephropathy typically present with renal insufficiency and anemia. Urinalysis reveals a few red cells and mild proteinuria. The rate of decline of renal function varies but may depend on the cumulative dose of AA. Renal histology is characterized by extensive interstitial fibrosis with tubular atrophy and low numbers of inflammatory cells. There is a very high incidence of urothelial atypia and carcinoma. Exposure to AA can be confirmed by the presence of AA-DNA in biopsy tissue. 

Therapy consists of routine management of CKD alongside regular screening for urothelial malignancy. A trial of steroids can be considered in selected patients. The risk of urothelial malignancy is so high that some consider patients for bilateral nephrouretecomy once RRT as been established.

Despite being banned in many countries, products containing AA remain available. The true incidence of CKD and urothelial malignancy resulting from AA exposure remains unknown. It is possible that a lack of awareness means that a significant proportion of AA resulted morbidity remains undiagnosed.  For a comprehensive review of the subject see here.

Image from Wikipedia.

Posted by Jonathan Dick

What are you smoking?

I recently saw an interesting case series published in CJASN where they reported four cases of oliguric AKI  associated with synthetic cannabinoids use. Renal biopsy revealed acute tubular injury in three of them and calcium oxalate crystals  in two.

Interestingly, around the same period of time I was rotating in nephrology consult service and had an elderly patient with history of paraplegia and neurogenic bladder (on intermittent self-catheterization), who was brought to the ER with altered mental status for which he was intubated for airway protection. On presentation, he was found to have acute kidney injury (Cr 6.0). His renal function continued to deteriorate with no specific etiology for his renal failure, so he had a renal biopsy which showed evidence of an active tubulointerstitial nephritis with marked tubular injury and calcium oxalate crystals present within the tubular lumina. Remarkable findings in his history included the recent use of cannabinoids. He never had history of renal stones. His home medication includes: methadone, oxycodone, nortriptyline and pregabalin. Admission labs showed normal osmolar gap and negative toxicology analysis. Urine microscopy showed muddy brown casts with no identifiable crystals.  Abdominal ultrasound did not reveal any renal calculi. Renal replacement therapy was started for uremic symptoms and he continued to require replacement therapy after his discharge.

The use of these synthetic cannabinoid preparations has increased significantly in the United States over the past few years, and the incidence of acute kidney injury (AKI) from use of these agents  is underestimated. CDC investigators have identified 16 patients (15 males; median age, 18.5 years) from 6 states who presented to emergency departments in 2012 with acute kidney injury after smoking a synthetic cannabinoid product.  Six patients had acute tubular injury and three had acute interstitial nephritis. Even though we can relate tubular injury and interstitial nephritis to the use of cannabinoids  , presence of calcium oxalate crystals was perplexing. In the case series reported in CJASN, they mentioned the presence of calcium oxalate crystals in two patients, but the mechanism of development of these crystals was not fully elucidated . We are hypothesizing that synthetic cannabinoids could be the potential cause for calcium oxalate deposition in this patient (after all causes of secondary hyperoxaluria were excluded). One possible explanation is that synthetic cannabinoids contain additional compounds which are plant in origin and these may be oxalogenic

Synthetic cannabinoids use should be in our differential diagnosis for unexplained AKI in young adult population as it can cause either ATN or AIN or both. A high index of suspicion is required as they may not be detected on routine urine drug screens.

Posted by Mahmoud Kamel

Renal Grand Rounds - Case of the month

A young woman with h/o polysubstance abuse and seizures was admitted to hospital with status epilepticus. She was treated with a propofol infusion at 5mg/kg/hr which was maintained due to perceived continuing seizure activity. On hospital day 5, she developed an acute metabolic deterioration – rhabdomyolysis : CPK 100,000, AG metabolic acidosis (HCO3 18) and non-oliguric AKI. Her EKG also became abnormal (RBBB). The diagnosis was propofol infusion syndrome.

What is propofol Infusion Syndrome (PRIS)? 

Like many syndromes, PRIS is a conglomeration of clinical and biochemical manifestations.  Based on  83 case reports from 1992-2007, PRIS is characterized by:

1) Metabolic acidosis, (pH less than 7.30 or HCO3 less than 19)

2) Rhabdomyolysis (CPK more than 10K)

3) Renal failure

4) Cardiac dysfunction (Brugada-like EKG pattern, asystole, PEA, sustained VTs, heart failure, or bradycardia) 

5) Hypertriglyceridemia (TG more than 400)

6) Hyperkalemia

7) Hypotension (or use of vasopressor agent)

8) Hepatic transaminitis

9) Hypoxia (PO2 less than 60mmHg). 

The first 5 manifestations are the most common. While there is no requirement for the number of clinical manifestations a patient must exhibit to meet diagnosis for PRIS, a prospective study showed that most patients exhibit at least 3 defining manifestations within 3 days of propofol use.  In the same study, the incidence of PRIS was found to be a low 1% --similar to other estimates.  However, PRIS is associated with high mortality, up to 30% in some studies. Moreover, because many of these manifestations are common, the presence of any of them could be attributed to another etiology, thus delaying diagnosis of PRIS.  For instance, in the case vignette, the initial rise of CK was attributed to seizure rather than PRIS.

Pathophysiology of PRIS

Inhibition of electron flow along the mitochondrial electron transport chain/ impairs oxygen utilization. Propofol or its metabolites inhibits fatty-acid oxidation leading to buildup of toxic fatty acid intermediates. As described in this nice review.

Risks of PRIS?

Critical illness (especially, CNS illness); Use of propofol dosage more than 4 mg/kg/hr —the usual adult maintenance dose is 0.3 to 3mg/kg/hr; duration of Propofol use greater than 24hr; exogenous cathecholamines and corticosteroids; poor intake of carbohydrate, see this reference.

Management of PRIS

Early recognition/diagnosis; Cessation of propofol infusion; Cardiopulmonary support; Hemodialysis (strongly advocated by expert opinion and outcome of case series).  However, there are no known RCT of use of renal replacement therapy in the treatment of PRIS.  Nonetheless, in case series, survivors of PRIS are more likely to have received HD/CVVH.  Therefore, prolonged use of HD/CVVH is worth considering by renal consult service.  Because propofol is lipophilic and has volume of distribution of 20-40L, it is poorly cleared by HD/CVVH, prolonged RRT is likely needed for PRIS management.

The patient in the case was treated with CVVH overnight, and then transitioned to intermittent HD.  At the time of her discharge, she was off HD with her Cr back to baseline.

See this previous post by Nate on PRIS.

Posted by Opeyemi Olabisi

Heavy Metal

The excellent drug development blog "In the pipeline" highlighted a fascinating phase 2 trial that is ongoing at the moment. Pentoxifylline is a methylxanthine phsophodiesterase inhibitor that has been used to treat peripheral vascular disease. It is also known to have anti-inflammatory properties and a recent Cochrane meta-analysis suggested that there may be a benefit in patients with diabetic nephropathy and albuminuria. The trial mentioned above is of an analog of one of the active metabolites of pentoxifylline called CTP-499. The clever thing about this molecule is that it is deuterated.

Deuterium is an isotope of hydrogen. Hydrogen typically has a single proton and no neutrons. Deuterium is a hydrogen atom with an added neutron. The thing that makes this interesting to drug companies is that it forms stronger bonds with other atoms than traditional hydrogen. As a result, liver enzymes take longer to break down a drug that has deuterium substituted for hydrogen and thus the half-life of a medication can theoretically be extended. There has been a rush recently to patent various drugs that have been "deuterated" although it is uncertain at this time whether or not this is going to be a successful strategy. There really are few safety concerns - the deuterated hydrogen would eventually form D2O or heavy water in the body prior to being excreted. Although too much heavy water would be deleterious, you would have to drink liters before you would see any adverse effects and the effect of these medications is likely to be minimal.

Which thiazide? - the debate continues

The debate about which thiazide diuretic to prescribe patients with hypertension has been going on for years without resolution and both HCTZ and chlorthalidone have their supporters. This topic has been discussed in the past on the blog with the general sense being the chlorthalidone may be better although the objective evidence was not very strong. Unfortunately, the trial that would answer this for good: an RCT of chlorthalidone vs. HCTZ, will never be done so we have to depend on observational trials, imperfect as they may be, to try and get the answer. The argument in favor of chlorthalidone relies on the longer half-life of the drug which allows once-daily dosing with 24 hour blood pressure control.

An article in Annals of Internal Medicine gives us a little more information to help make an informed decision. The authors reviewed the records of 10000 patients in Ontario treated with chlorthalidone between 1993 and 2010. These were matched using a propensity score to 19000 patients treated with HCTZ and all were followed for a maximum of 5 years. All patients were over the age of 66 at the time of starting the diuretic and patients who had a major CV event in the year prior to entry into the study were excluded. The primary outcome was CV death or a major CV event. The authors believed that they were going to demonstrate a significant benefit for chlorthalidone. The overall results of the study are shown below:

There was no difference in the primary outcome between the two groups. In a safety analysis, the use of chlorthalidone was associated with a threefold higher OR for admission with hypokalemia and almost double the OR for admission with hyponatremia. There was no difference in the risk of all-cause hospitalization. The dose of chlorthalidone available on the formulary in Canada is 50mg daily so the thought was that this difference may be related to the use of higher doses but a post-hoc analysis showed that, irrespective of the dose used, chlorthalidone was associated with a higher risk of hypokalemia and hyponatremia. Looking back, this makes sense. The half-life of chlorthalidone is so much longer than HCTZ that potassium wasting is almost guaranteed. In fact, it has been shown in the past that chlorthalidone causes potassium wasting at much lower doses than HCTZ. Technically, HCTZ should be given twice daily because of the short half-life but it generally is not. I wonder if it was, would you see the same effect on electrolyte concentrations?

There is (as always) a caveat. There may have been some unmeasured confounding. It is uncertain why some physicians may have chosen chlorthalidone over HCTZ. The other formulation of chlorthalidone that is available in Canada is a combination drug with atenolol. As a result, the rates of use of B-blockers was higher in the chlorthalidone group and the rate of the use of ACEi was lower. This is a really interesting study. I have been tending to use more chlorthalidone in my practice over the last few years based on the limited that that were available but I am not sure what the correct answer is now. It should be noted that the UK guidelines now recommend thiazides as a 3rd line therapy for hypertension following CCBs and ACEi.

This is a great interview with the first author of the paper on Medscape which is worth reading.

New potential drug targets in ADPKD

Currently there is no good treatment for the most common inherited cause of ESRD, adult polycystic kidney disease. There have been a number of high profile trials in ADPKD in recent years. These trials have endeavored to show a reduction in cyst growth and GFR decline with everolimus, sirolimus) and most recently Tolvaptan (TEMPO). The longer (2years) and larger (433 patients) of the two mTOR inhibitor trials (everolimus) did show a significant reduction in cyst growth at one year but not in GFR reduction. The shorter sirolimus trial failed to show a reduction in cyst growth or GFR decline. The TEMPO trial was over 3 years, had 1445 patients and did show that the V2 antagonist Tolvaptan slowed GFR decline (reciprocal of the serum creatinine level, −2.61 [mg per milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; p=0.001) and cyst growth, 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0). The jury is still out about the clinical applicability of these drugs and there have been criticisms. For example, tolvaptan is very expensive and would need to be used long term. In the mTOR inhibitor trials some argue doses could have been higher and the lack of hard end points speaks for itself.

However, all is not lost. A potential new drug target in ADPKD was reported by Rowe et al. in Nature Medicine last month. A good overview of the topic can also be found in the same issue.

Using MEF cells from pkd-/- and pkd+/+ mouse littermates they found that growth medium from the pkd-/- cells was more acidic and that the pkd-/- cells had a higher ATP content. To investigate which metabolic pathways might be causing this difference they used NMR spectroscopy and found lower glucose and higher lactate levels in the knock out cells. They then used a mitochondrial ATPase inhibitor to determine the source of higher ATP and found only wt cell had a reduction in ATP with this treatment.  Then the investigators did a real-time PCR analysis on the pkd-/- cells and found an upregulated glycolysis signature. They thus concluded that the pkd-/- cells rely on aerobic glycolysis for their energy demands. This is known as the Warburg effect described in cancer cells (Otto Warburg, a physician-scientist, received the Nobel Prize in Physiology or Medicine in 1931). To see if these in vitro findings translated into in vivo they used Ksp-Cre; Pkd1flox/− mice, which develop early and severe PKD and measured 13C-glucose or 13C-lactate using 13C-NMR. The findings were the same. The authors then used 2-deoxyglucose (2-DG) an analogue of glucose that is unmetabolised. They treated wt and pkd deficient mice this compound and found that the pkd deficient mice had a lower cyst index and lower 13C-glucose consumption as measured using 13C-NMR.

This interesting study proposes that the use of drugs targeting this pathway in combination with other drugs may reduce cystogenesis and progression of CKD in ADPKD. The authors do stress that their summary with regard to human treatments is speculative. In all I think the future is not so gloomy for ADPKD.

Posted by Andrew Malone

Bad Odor

Cystinosis is an autosomal recessive disease caused by a mutation in CTNS, which encodes the lysosomal transporter of cystine. This leads to intracellular cystine accumulation which leads to renal, neurological and cardiac damage. The treatment for this condition is life-long cysteamine. Back in 2011, we reported on a new formulation of cysteamine that is given just twice daily (rather than q6 hours) and is associated with a lower incidence of side effects including halitosis and body odor. There was a higher incidence of GI side effects in patients treated with the new drug. The halitosis occurs because a proportion of the drug is converted to dimethylsulfide and this can appear in expired air. The reason why the new formulation is associated with less halitosis is because, although serum drug levels are the same as with the older drug, the total dose is reduced so there is less overall conversion to the offending metabolites. This is welcome news for patients given that the drug should be started before age 5 and the halitosis and body odor cause major social problems for patients which can result in non-compliance.

Yesterday, the FDA approved cysteamine bitartrate ER (Procysbi) for the treatment of cystinosis. Essentially, this is an enteric-coated delayed-release version of the drug that is largely absorbed in the small intestine. The major issue, of course, is cost. The traditional form of the drug costs about $8,000/year while the new formulation will cost approximately $250,000. That is an enormous difference for a drug which does no more than reduce side effects. However, when you read this New York Times article on procysbi, you can better understand why the parents of these children think that this is entirely worth it.

According to the same article, it is estimated that by 2018, spending on orphan drugs will account for about 16% of overall spending on prescription drugs. This is bound to lead to conflict between insurers, patients and the manufacturers when trying to decide who to treat and who will pay. Is it worth $242,000 every year for a drug to be given twice, rather than four times daily? The problem, of course, is that this is the only way that the company can recoup the cost of development because there are so few patients with the disease - approximately 300 in the US. It should be remembered, of course, that the ulitmate cost of non-compliance in this case is very high - dialysis, transplantation and loss of future earnings so the cost calculation is not as simple as I suggested above. This is a debate that is certainly going to continue over the next few years.

Falsification Analysis

Interesting paper this month in JAMA about post-marketing studies of adverse drug effects. Randomized controlled trials are obviously the gold standard for the detection of common adverse events related to treatment. The problem is that, if an adverse event is rare, it is unlikely to be detected by a normal RCT. As a result, there has been a move recently towards conducting post-marketing studies of commonly used drugs to identify rare adverse effects. One such effect mentioned in the study is the association between bisphosphonate use and atypical femoral fractures.

The other commonly cited example recently was the association between PPI use and community acquired pneumonia that has been noted in multiple studies. The putative mechanism is that it is due to a reduction in gastric pH. The problem is the question of residual confounding - is there an alternative reason that these patients have more pneumonia. Are these patients simply sicker overall? Are PCPs who prescribe PPIs more likely to diagnose pneumonia? Just because there is a plausible mechanism doesn't make it true.

One potential solution is to perform a falsification analysis. Once you have determined the primary outcome of the study (in this case pneumonia) with a plausible outcome, you then perform a series of prespecified analyses with other non-plausible outcomes. If all of the outcomes are associated with the use of PPIs, it suggests that the association is more likely related to residual confounding rather than a real effect.

In the study referred to in the JAMA article, the authors, working from registry data, not only found an association between PPI use and pneumonia but also with osteoarthritis, urinary tract infections, rheumatoid arthritis, chest pain, DVTs and skin infections. Thus, they suggested that the association with pneumonia was more likely to be confounded because of the lack of a plausible relationship with these other adverse events. One criticism I would have is that I could think of perfectly reasonable hypotheses for why PPI use could be associated with OA and RA (use of NSAIDs) and chest pain (GERD). Another important point is that if this is not done properly (prespecified adverse events) you could find an association between the use of a drug an some adverse event if you tested enough and it could be used to wrongly refute the association between a drug and a problem.

Still, the whole article is a fascinating insight into the problems with post-marketing studies of drugs in the wider population.

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 

Bardoxolone - The final chapter?

Sometimes when something appears too good to be true, it is too good to be true. Last year, a paper was published in the NEJM reporting a preliminary study of bardoxolone for the treatment of diabetic nephropathy. At the time, this seemed like it might be promising but there were a number of issues with the study including the use of eGFR as an endpoint and the fact that the use of the drug was associated with a significant rise in albuminuria, both of which we raised here in a blog post. More recently, we posted again on this drug. An experiment in monkeys revealed that bardoxolone downregulated the expression of megalin in the proximal tubule and that this may have been responsible for the increase in albuminuria.

All this time, a phase 3 study was ongoing to determine what the true effect of the drug was in a larger group of patients. Unfortunately, it was announced last week that the trial had been stopped. According to an article in marketwatch, there were "excess serious adverse events and mortality in the bardoxolone methyl arm" according to the monitoring committee. We don't know yet what exactly happened and the company is not releasing any more data beyond this simple statement. I am sure more information will come out in the future.

This is extremely disappointing. For all that it seemed too good to be true, there are so few things that we have in our toolbox to delay the progression of diabetic kidney disease that this was potentially a blockbuster treatment for this condition. There may be aspects of this drug that remain useful in some specific circumstances and it may also aid in future drug development. We will not know the answers to these questions until the final study results are published.

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