Nephrology Madness: Meet the competitors for Loop of Henle Region’s Thick Ascending Limb

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(1) Captopril vs (16) Epoetin Alfa

A battle of the elites. Captopril is representing all of the anti-angiotensin II drugs.  Its always nice to be the go to drug with proven mortality benefits. However, epo is a formidable foe but its enthusiasm in recent years is waning and they barely made the tournament.

Captopril

If captopril was a basketball team they would be the Vipers. Angiotensin converting enzyme inhibitors (ACEi) had been theorized and many drug developers were looking for candidate molecules. John Vane, the Englishman who won the Nobel prize for discovering the mechanism of aspirin and defining prostaglandin physiology, learned about the venom of the Bothrops jararaca viper that induced death via a massive drop in blood pressure. He secured snake venom and his team discovered that the mechanism was inhibition of angiotensin converting enzyme. They later isolated a 9 peptide derivative of the venom that was actually used in human trials for hypertension and heart failure. The peptide had to be given parenterally since it was not stable orally (See Gavras et al). Vane took this discovery to the pharmaceutical company Squibb, where scientists, David Cushman and Miguel Ondetti, began searching for an orally stable ACE inhibitor. Ultimately they modified a carboxypeptidase inhibitor to resemble the functioning ACEi and created captopril. This is one of the early examples of structure-based drug design (See Patlak).

Bothrops jararaca viper. Image Credit: Felipe Süssekind

Epoetin Alfa

In June of 1989 the transfusion rate for dialysis patients was 15.8% every three months. By March of 1990 that had fallen to 6.6% and by December 2000 that had fallen below 1%. This night and day change in the transfusion rate in patients receiving hemodialysis is a tribute to the use of epoetin alfa and the scientists and clinicians at Amgen who brought it to market. Today, it is nearly impossible to recondition your mind to think about what it meant to dialysis patients to be receiving recurrent blood transfusions every few months. The country was in the middle of the AIDS epidemic and though an antibody test existed, PCR for viral load was not available, meaning no transfusion was completely safe. A drug that could reduce transfusion requirements was not just a convenience it was a life line. The other benefit to the fall in transfusions was the decrease in antigen exposure to patients on the wait list for kidney transplantation. Through the ‘90s and ‘00s the proportion of unsensitized patients on the kidney transplant wait list roughly doubled from 25 to 50%. This decreased sensitization is a direct result of the decreased transfusion dependence in patients on hemodialysis. Though our relationship with the miracle of epoetin alfa has been tarnished of late it is difficult to imagine nephrology without it.

(3) Mycophenolate Mofetil vs (14) Cyclophosphamide

“The battle everyone wants to see is MMF against cytoxan.”
–early discussion among the selection committee.

Mycophenolate Mofetil

Mycophenolate Mofetil (MMF) began life in transplant and earned its stripes in a randomized controlled trial against azathioprim, where it showed decreased acute rejection. However, this may have been an illusion, as recent studies have not been able to replicate these successes.

The jump to glomerular nephritis is where MMF is changing nephrology. First in lupus where MMF was shown to be equivalent to cyclophosphamide for induction and maintenance  therapy. MMF has consistently showed non-inferiority to cyclophosphamide in lupus.  A meta-analysis published in the AJKD also supported MMF vs. cytoxan with less ovarian failure and alopecia, major sources of morbidity.

MMF is finding some success with membranous, ANCA vasculitis and MPGN.

Cyclophosphamide

Cyclophosphamide is the Hannibal Lecter of drugs, a drug with a side effect profile almost perfectly created to make it not just dangerous but cruel. Like all alkylating agents, cyclophosphamide causes bone suppression, increases the risk of hematologic malignancies, alopecia, ovarian failure, and teratogenicity, but cytoxan has a couple of unique properties that propel it above and beyond the typical bad actor.

Cyclophosphamide causes bladder cancer. And it can cause bladder cancer decades after the drug has been stopped (see Radis et al.) The poor patient may have stopped the drug 15 years ago, the prescribing doctor may have retired and moved to Boca when the cancer breaks through (see Monach et al). To make matters worse, the conventional GU cancer screen, urinalysis for hematuria is not so helpful in cyclophosphamide whose patients usually have glomerular hematuria at baseline.

Additionally cyclophosphamide causes hemorrhagic cystitis. The standard advice for this is to encourage drinking inorder for patients to maintain a brisk urine flow so that the cyclophosphamide is not in contact with the urinary epithelium for long. This would be great advice if cyclophosphamide didn’t have ADH-like activity. Increased water intake can turn around and predispose the patient to life threatening acute hyponatremia. This has even been seen in low dose cyclophosphamide IV and PO. (see Salido et al and Kato et al) Would you like some fava beans and chiante with that lupus therapy?

(12) Rituximab vs (5) Eculizumab

Now this is an interesting battle.  The basic question is what’s better – stopping antibody production with rituximab or blocking the effector pathway with eculizumab?  Let’s look at the data and make some wagers. [editors note: please no wagering]

Rituximab

Rituximab is a monoclonal antibody directed against CD20 which is found on B cells.  It was born in the field of oncology and gained fame in the treatment of various B cell lymphomas.  It made its way into nephrology as an answer to diseases attributable to antibody mediated injury.  In transplantation rituximab has been used to treat antibody mediated rejection.   It has also been used in combination with intravenous immunoglobulin to improve transplant rates in patients with anti-HLA antibodies (desensitization of the highly sensitized patient).    In addition it has also made its way into the arena of glomerulonephritis.  Rituximab has been used to treat membranous nephropathy, lupus nephritis, recurrent FSGS post transplantation and pauciimmune glomerulonephritis.  But does it really work?  Most of the mentioned trials are not placebo controlled and involve a very limited number of patients.  In addition rituximab may target B cells but not long lived plasma cells which produce antibodies and are CD20 negative.  Finally it clearly increases the risk of serious infections.  Though rituximabs gained much fame in the nephrology community not everyone is a fan!

Eculizumab

Eculizumab is a monoclonal antibody that inhibits C5.  Without C5 you prevent the formation of the MAC complex and stop the most potent pathway of complement mediated cell injury.  Not only does this stop the effecter pathway of antibody mediated injury, but it also prevents injury from the disorders of complement dysregulation.  Case in point – this drug has revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH).  In fact it is the only drug that is FDA approved to treat it.  In nephrology it has revolutionized the treatment of atypical HUS where it is also FDA approved.  It is even being studied in kidney transplantation to prevent and treat antibody mediated rejection.  Again, antibodies cant do much damage if you block complement.  However, we need to remember that eculizumab is still a rooky in nephrology.  The diseases it is approved for are quit rare and it is not clear when, if ever, the drug can be stopped.  Perhaps equally important is that this drug does not come cheap.  One year treatment for atypical HUS in an adult costs about $500,000 – now that’s an expensive contract!

(7) Cyclosporine vs (10) Tolvaptan

This will be an interesting battle.  Cyclosporin is a true veteran.  Been there done that.  Its side effect profile is well know and it is generic. Tolvaptan is just beginning to receive accolades and is expensive, new and unclear toxicity.  Lets take a closer look.

Cyclosporine

Cyclosporine has been a mainstay drug in transplant nephrology for many years. Only recently has tacrolimus (FK506, Prograf) supplanted its use. The drug was first isolated from the fungus Tolypociadium inflatum contained in a soil sample obtained in 1969 from Hardangervidda, Norway. However, the immunosuppressive effects were unknown until 1972 when employees from Sandoz in Switzerland discovered its effects. The first description of its use in solid organ transplants was in a cadaveric kidney transplant discussed in a paper in the Lancet from 1978. This paper described 7 patients  receiving cyclosprin A after kidney transplant. The characteristic nephrotoxcitiy was evident even at this time. The primary mode of action of this drug is to lower the activity of T cells by inhibiting calcineurin which in turn decreased IL-2 production. The drug was a mainstay for many years after the seminal 279 patient trial was paper published in the NEJM in 1994.

Tolvaptan

Tolvaptan is the new kid on the block in the nephrology world. The drug is a competitive vasopressin receptor 2 antagonist. The vaptan class of non-peptide vasopressin antagonists were developed in the mid 1990s. These molecules competitively block the binding of vasopressin to V2 receptors on renal collecting duct cells. The first large scale clinical trials to use the vaptan class of drugs were Study of Ascending Levels of Tolvaptan in Hyponatremia or SALT 1 and 2 trials.  These were published in the NEJM in 2006. However, concerns about costs and potential liver toxicity remain for this indication.  More recently Tolvaptan made a splash at Kidney Week 2012 when the results of TEMPO 3:4 clinical trial were released showing decreased cyst growth and slower progression of loss of GFR in autosomal dominant polycystic kidney disease (see Torres et al).

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