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Aristolochic Acid versus Fomepizole
Winner: Aristolochic Acid
Graduates of the Aristolochic Acid college are enjoying quite a season. How is a Toxin able to fare this well in a tournament filled with remedies, guidelines, and therapies? How is this possible? Well, Aristolochic Acid is quite the demon that needs to be reined in. The International Agency for Research on Cancer and the World Health Organization (WHO) have labeled Aristolochic acid as a type I human carcinogen. This hasn’t stopped its use. It is an undeclared ingredient in up to 20% of Chinese herbal products. You got that right. 20%. This is a crazy statistic as Aristolochic acid could be the cause chronic kidney disease in a majority of patients in Asia. And with the population of China being so large, this is a big deal. So Aristolochic acid is worth remembering as it is not just a “board question”. Fomepizole was way to expensive of a drug to maintain. The use of alcohol itself to compete with ethylene or diethylene glycol, methanol or propylene glycol is really an option. For this reason, fomepizole just couldn’t pull it out. Aristolochic Acid goes on to face its arch nemesis DSHEA 1994.
Glycyrrhizic Acid versus DSHEA 1994
Winner: DSHEA 1994
Team Dietary Supplement Health and Education Act of 1994 (DSHEA) represents the FDA’s major defensive strategy in the management of the marketing and distribution of vitamin and herbal supplements in the US. DSHEA is a landmark federal legislation that guides the government’s role in the regulation of herbal and vitamin supplements. The history of this act is important to truly evaluate the impact it has had on pharmaceutical safety and financial success of the supplement industry. Let’s review some of the scouting report from Dr. Kupin:
Prior to 1962, the FDA was not required to evaluate the efficacy and claims of any drug or supplement marketed in the U.S. The 1938 Food, Drug and Cosmetic Act only mandated that the drug companies demonstrate to the FDA that their drug was safe. However there was no regulation of advertising claims or any requirement of efficacy. The tragic thalidomide birth defects in Europe, however, forced an overhaul on the operations of the FDA. The Kefauver Harris Amendment or “Drug Efficacy Amendment” of 1962 required all manufacturers to provide proof of effectiveness of all drugs sold. An exemption to the Kefauver Harris Amendment was passed in 1994 called the Dietary Supplement Health and Education Act (DSHEA). This change in the law allowed all vitamin and herbal supplement manufacturers to be exempt from FDA review.
The DSHEA 1994 act remains the most important factor influencing the sale, control, and advertisement of Alternative Medicines in the US. We need to start regulating these agents as deleterious side effect are bound to continue. DSHEA 1994 moves to the next round to play Aristolochic Acid. This will be the test we have been waiting for. We need to find a way to regulate these and unfortunately DSHEA 1994 is not that way.
Check out the entire Toxins SCOUTING REPORTS and FIRST ROUND RESULTS from eAJKD
Renal Artery Therapies versus Systolic Blood Pressure
Winner: Systolic Blood Pressure
Systolic blood pressure takes the victory from the injury prone renal artery therapies. This was not really a surprise as systolic blood pressure has been the target of therapy and epidemiology studies since the beginning of medicine. Nobody can rival the dominance of systolic blood pressure in this field. Renal artery therapies has had a rough couple of years. First, we get the CORAL trial showing that revascularization of of renal arteries with stents did not confer a significant benefit compared to medical management. Then we have the SYMPLICITY trial. This was the biggest letdown of the year for hypertension research. The anticipation was palpable. A press release late last year hit with a thud. BP effect was not as great as anticipated. The results of the SYMPLICITY trial will be reported at ACC2014 on Saturday. We will update you on the results of this trial. Next up for Systolic BP is JNC8. The much awaited guidelines to reduce the prowess of Systolic BP.
Chlorthalidone versus JNC8
The Chlorthalidone fan club will surely be disappointed with the demise of Chlorthalidone to JNC8. JNC8 was was way to “streamlined” to deal with. The guidelines shaved off considerable bulk from the JNC7 predecessor. JNC8 attempted to simplify management of hypertension buy recommending Systolic BP to be below 150/90 in those over the age of 60 and 140/90 for all others; similarly, they also simplified the drug regimen, that is, ACEi, ARB, calcium-channel blockers (CCB), and thiazide-type diuretics are reasonable choices, to get patients to goal SBP. In the era of personalized medicine some argues that this was a ‘oversimplified approach.’ JNC8 does a number of other things.
- define the target BP thresholds for initiation of pharmacological intervention, eg, decrease blood pressure to <150/90 mm Hg in patients aged ≥60 or older and a DBP <90 in those aged 30 to 59
- recommend a broader range of anti-hypertensive agents for initial treatment in non-blacks, including those with diabetes
- recommend ACEi or ARB for all patients with CKD with or without DM regardless of race.
Unfortunately, it was difficult for Chlorthalidone to dethrone a massive guideline document. This is unfortunate indeed. Chlorthalidone has a longer half-life and larger volume of distribution allowing the drug to achieve a more evenly distributed BP control throughout the day as compared to hydrochlorothiazide. This is why they won round one. Now it is a battle of the beast (SBP) and the beast master (JNC8). Tune in this weekend to see!
Check out the entire Hypertension SCOUTING REPORTS and FIRST ROUND RESULTS from eAJKD
Diffusive Clearance versus Residual Renal Function
Winner: Residual Renal Function
Residual renal function is looking to really make waves in this years NephMadness. Seems like we are always preaching to other services to “preserve the residual renal function”. This teams needs to be mainstream. Like avoiding NSAIDs, contrast if possible and keeping low blood pressure at a minimum. Interesting that residual renal function’s arch nemesis contrast nephropathy is still alive and well. Why should we care about residual renal function. As discussed in detail in the original scouting report, residual renal function lowers B2 microglobulin, potassium, aluminum levels, raises bicarbonate and improves phosphate balance. Residual renal function is important contributor to patient health. Here is what Andrew Howard and Klemens Meyer, President Elect and President of the ESRD Networks, had to say:
The requirement to exclude residual renal function from reported Kt/V presents those facilities which choose to measure residual renal function with a dilemma: either accept a QIP penalty for supposedly (but not really) inadequate dialysis, or coerce the patient to accept a medically unnecessary prolongation of treatment time. This hardly sounds like patient-centered care, and we suggest that as written, the proposed Rule fails fairly to answer the question “How did the patient do?”
Residual renal function is a contender to win it all. Unfortunately, diffusive clearance hit a wall. The convective clearance bandwagon was extremely disappointed to lose the first round against the wily diffusive clearance team. Diffusive clearance has been tinkered with for years without any improvements in mortality. Just look at the HEMO study. Middle molecule clearance is the future. Studies are starting to roll out. Like this study from Spain published in JASN in 2013. Unfortunately, the future is not yet here. We await big randomized trials for convective clearance. This is the end of the road for diffusive clearance. Up next for team residual renal function is Urgent Start Peritoneal Dialysis.
Urgent Start PD versus DreamRCT: ESRD
Winner Urgent Start PD
Urgent Start PD continues to dominate NephMadness. The ability to start patients on peritoneal dialysis immediately after placement of a peritoneal dialysis catheter has really increased the number of patients using this modality. This is especially good news in the US where the utilization rates of PD are much lower that other counties. This is described by Ghaffari et al in AJKD eloquently. PD is a great option for many patients as patients have much more freedom and autonomy and they can travel much easier. Urgent Start PD is starting to sweep the US. This is a much needed initiative and frankly quite opposite of many of the initiative performed before to try to boost interest in PD. The Sweet 16 battle of Urgent Start PD versus Residual will be something to watch for sure. Unfortunately, for the Dreamer’s out there, DreamRCT: ESRD just couldn’t knock off Urgent Start.
Check out the entire RRT SCOUTING REPORTS and FIRST ROUND RESULTS from eAJKD
Parietal Epithelial Cells versus Renal Pericytes
Winner: Renal Pericytes
Team pericytes takes the victory over parietal epithelial cells (PECs). This is an interesting matchup as both of these cell types were the forgotten cell type a decade ago. Now there is renewed interest and much more research is being performed. This is a battle of the P’s. How did the pericytes edge out the PECs? While is has been shown that PECs are starting to gain traction in a variety of glomerular diseases such as FSGS or rapidly progressive glomerulonephritis, team pericyte might be involved in the eventual march to fibrosis and end organ damage that are common to all of CKD including diabetes! This gives the edge to team pericytes. They also could play an important role in repair and the fibrotic response to acute kidney injury.
Tubule Regeneration from Resident Stem Cells versus Bioartificial Kidney
Winner: Bioartificial Kidney
Was there ever a doubt that Bioartificial Kidney wouldn’t make it to the Sweet 16. Team Bioartificial Kidney is an amalgam of everybody in the regeneration bracket all rolled into one superstar team. They are the Kentucky of NephMadness. A team filled with one-and-dones. The problem with team Bioartificial Kidney is that the initial report, however impressive, fell short of actually being able to sustain the life of the animal it was implanted into. Also, the results have not been replicated. We are still a long way off from being able to even think of doing something like this in humans. Resident Stem Cells of the kidney barely squeaked by its first round contender Self-duplicating Tubules. This is because mounting evidence has been mounting that self-duplication might be the process that occurs instead of the the proliferation of resident stem cells. Next up for Bioartificial Kidney with be the prolific fibroblast-making team Pericyte. This will be a prime-time battle that will surely not disappoint. Vegas is a buzz about this one.
Check out the entire Kidney Regeneration SCOUTING REPORTS and FIRST ROUND RESULTS from eAJKD
Contrast Nephropathy versus Urinalysis and Indices
Winner: Contrast Nephropathy
Contrast Nephropathy takes the win over Urinalysis and Indices. The first thing done when you receive a consult is to graph out the creatinine and place times where contrast was given. See if it lines up. From the round 1 game analysis:
Contrast-Induced AKI leaves a long lasting impact on its opponents who are rarely able to completely recover and perform back at their full capacity accompanied by an accelerated development of CKD in their future. Both short and long term mortality is markedly increased after Contrast-Induced AKI is present.
It is clear that Contrast Nephropathy is something for its opponents to fear. Urinalysis and Indices are a staple for nephrologist. Everyone with AKI gets these. In fact, we demand they be done well in advance. Here are some of the weakness in team Urinalysis and Indices as noted in the scouting report.
Once considered to be the star player FENa has had a challenging time when faced against a team that uses diuretics, CKD, or heme pigment toxins. In addition, FEUrea has similarly slowed down over the years having a very difficult time in sensitivity (61%) and specificity (59%) in ICU patients.
So what is next for Contrast Nephropathy. Next up is Balanced Solutions. What, no Normal Saline? I know, I know. Duke and Normal Saline lost in the first round. Just not their year. Balanced Solutions have a new coach and their critics are starting to like them again.
Balanced Solutions versus KDOQI AKI
Winner: Balanced Solutions
Now, what is up with Balanced Solutions. Are they really all that? Lets look at the scouting report:
This team has labored in the shadow of Fluid Resuscitation: Normal Saline for years and has yet to breakthrough into the mainstream. In order to change the prescribing patterns of physicians, Balanced Solutions knows that they will need concrete evidence and a blockbuster study to support their cause. So far things are looking promising at the bench research level. Compared to their arch nemesis Normal Saline, Balanced Solutions resulted in improved renal blood flow and a reduced risk of AKI. Clinically, even better news is on the horizon as Balanced Solutions own an early victory in comparison with Normal Saline in critically ill patients for the prevention of AKI.
Team Balanced Solutions still has a long way to go in order to gain widespread popularity. They are from an outside conference looking in. We need a large randomized controlled trial comparing different solutions. KDOQI AKI had a great run but ultimately fell short. Ultimately, AKI guidelines just couldn’t beat the recent surge of Balanced Solutions. Up next is a battle with Contrast Nephropathy.
Check out the entire Acute Kidney Injury SCOUTING REPORTS and FIRST ROUND RESULTS from eAJKD
Hypertonic Saline versus Serum Anion Gap
Winner: Serum Anion Gap
This was a very interesting matchup. It is true that hypertonic saline has been a life-saving therapy in the treatment of hyponatremic emergencies; however, the sky is the limit when you think about the uses one can give to serum anion gap: uncovering acid-base disorders even when the pH is normal (eg, pH=7.4, pCO2= 40, HCO3=24, Na=140, Cl=80), alerting us of the hidden toxic alcohol ingestion, diagnosing a monoclonal gammopathy when low or negative values are found. There is no comparison! One must still consider the limitation of SAG. This round goes to serum anion gap.
ZS-9 (novel potassium binder) versus Bicarbonate in CKD
Winner: Bicarbonate in CKD
Even though ZS-9 seems to be the long-sought solution to the problem of dealing with hyperkalemia in a safe manner, their lack of use in practice makes ZS9 just an illusion for now. On the other side, bicarbonate comes highly recommended since it has been around for decades. Its minimal sodium retention properties and recent evidence for its use in slowing progression of CKD makes bicarbonate in CKD the winner of this matchup. I’m sure we will hear from ZS-9 soon. Frankly, I’m a little surprised that the results still haven’t been published. Next on the chopping block from Bicarb in CKD is the venerable team SAG. Can bicarb stuff the gap and move on to the Elite 8? You will have to tune in to see.
Check out the entire Electrolytes SCOUTING REPORTS and FIRST ROUND RESULTS from eAJKD
Medical Care of Acute Stones versus CT scan
Winner: Medical Care of Acute Stones
To everyone’s pleasure Medical Care of Acute Stones (MET) is still alive. This is important and often overlooks topic in the Stone world. Let’s go back to the scouting report by Dr. Goldfarb and see exactly what we mean about this.
One of the primary concerns of MET is pain control. Opioids and NSAIDs both can be used. In a single center RCT, the combination of ketorolac and morphine was better than either drug alone. NSAIDs may have an additional benefit by reducing ureteral edema than can impede stone expulsion.
Additional agents include alpha blockers (tamulosin, doxazosin) and calcium channel blockers (typically nifedipine) which are both effective at increasing the success and reducing the time until the stone is cleared. In a meta-analysis of 9 studies (693 patients) use of these drugs had a number-needed-to-treat of only 4 to get an additional stone expulsive. In addition, steroids may have a role, either alone, or more commonly in conjunction with one of the above agents. The steroids, may have act just like to NSAIDs to reduce the edema and ease stone passage.
This is an important topic to highlight and discuss as it can really impact the life of a patient. The radiation exposure of the CT Scan was its limiting factor in allowing to continue in NephMadness. It’s overuse cannot be understated and it was time to put an end to its dominance. MET did just that. Next up is Oxalobacter formingenes. This will be a true test.
Dr. Fred Coe versus Oxalobacter formigenes
Winner: Oxalobacter formingenes
Oxalobacter formigenes beats out Dr. Coe. Dr. Coe led to a revolution in how we think of stones and his influence continues. No disrespect from the NephMadness team. Team Oxalobacter are the new kids on the block. Lets look at the scouting film:
Oxalobacter are anaerobic gut bacteria that metabolize oxalate, the critical urinary metabolite in calcium oxalate stones. If you are colonized with these bacteria, you absorb less oxalate than someone with a similar diet who is not colonized with oxalobacter. People colonized with oxalobacter can plow through cans of spinach like Popeye on a bender and their urinary oxalate doesn’t budge. Siener et al found a tight dose response, such that patients with stone recurrence are much less likely to be colonized with Oxalobacter and the relationship becomes tighter and tighter as the number of stone episodes rises. Unfortunately, attempts to seed stone formers with oxalobacter have not shown consistent benefit.
The addition of this probiotic could become a major player in the kidney stone prevention world. For these reasons they won the first and second rounds. Next up is MET in the Sweet 16.
Check out the entire Kidney Stones SCOUTING REPORTS and FIRST ROUND RESULTS from eAJKD
Rituximab versus Belatacept
This is the big biologic battle that you have been waiting for! Yes, the favorite of many in Nephmadness is rituximab. At this point, it is the most popular contender in the contest. But let’s bring to light some major newer side effects this agent can lead to. Newer studies now showing rituximab-induced lung disease, rituximab induced coronary spasms and a vast review of long term side effects with this agent. While rituximab is used in transplantation, it’s more of a rescue agent. In general nephrology, it has become a major player. In the last 10 years, belatacept has been a true breakthrough in the transplant literature. It is the only way to minimize calcineurin-related CKD in our transplant patients (seriously, there isn’t anything else out there). And it’s sister drug (abatacept) is making recent news again in NEJM this week. It can be upsetting to see the Yankees lose to the Mets or Brazil get beat by a new team in the FIFA world cup or Duke getting beat in the first round by Mercer. It has happened now in NephMadness: Belatacept out does Rituximab in this round to march on to the next round to face Eculizumab.
Eculizumab versus ACTHar Gel
Should we shock you more?? ACTHar Gel while had some earlier success in Italian studies, the use in US has been based on few observational trials only in proteinuric diseases. Eculizumab on the other hand has really changed a pathway of treating diseases: use of the alternative complement inhibition to combat many autoimmune diseases: atypical hemolytic uremic syndrome, membranoproliferative GN, C3 glomerulopathy, and dense deposit disease. And many more to come? Given it’s role in complement inhibition, we won’t be surprised that it can be used in transplant rejection, ANCA-associated kidney disease and other autoimmune disorders. Clearly, a new class of agents that has more long term potential than ACTHar Gel. Eculizumab wins over and proceeds to the next round to face Belatacept.