Eculizumab dosing in aHUS patients undergoing kidney transplantation

Hemolytic uremic syndrome is a thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic hemolytic anemia and renal impairment. Most cases (90%) are secondary to infections, such as E. Coli (serotypes O157:H7, O103:H2). For a more comprehensive review about aHUS, check this paper. The rest of the cases are classified as atypical uremic syndrome (aHUS), which is typically associated with a poor prognosis. There is a previous post about Eculizumab and renal transplantation on the RFN.

The majority of the patients with aHUS are affected during childhood and teenage years to the point of developing kidney failure. When kidneys are severely involved the best treatment option is kidney transplantation. These patients are at high risk for recurrence of the disease after transplantation and a high percentage of these patients lose their kidney allografts. In patients with mutations in Factor H and Factor I, recurrence occurs in about 70-80% of the cases. Other less common mutations associated with recurrence, are C3 and FB. Furthermore, it has been reported that mutations in the MCP (membrane associated regulator, CD46) gene are less likely to be associated with recurrence, because the mutation affects the endothelial cells and renal transplantation would restore normal endothelial MCP function in the kidney. 

Eculizumab is indicated for the treatment of paroxysmal nocturnal hemoglobinuria and aHUS. It is also used in ABO-incompatible living donor kidney transplantation and antibody mediated rejection. This monoclonal antibody binds the complement protein C5, blocking its cleavage into C5a and C5b, hence preventing the formation of MAC. The authors of this paper concluded that eculizumab was effective in patients with aHUS and native kidneys. I found approximately 15 adult cases reported in the literature that received prophylactic eculizumab to prevent post-transplant aHUS suggesting that this approach is effective. However there are no standardized protocols for administration of the drug preoperatively. In these cases, patients received a dose of eculizumab 1,200 mg IV 24 hours prior to transplantation, and after transplantation 900 mg IV weekly for 4 weeks started on post-operative day 1, and then 1,200 mg IV bi-weekly afterwards. This is based on the manufacturer’s recommendations. There are also pediatric cases and the majority of them have had successful transplantation without recurrence of aHUS. All of these case reports, have used different pre-emptive protocols. In one case , the patient was started on eculizumab 7 months prior, receiving 600 mg as the initial dose, followed by 300 mg every two weeks thereafter. In another case, eculizumab was given 2 hours prior to kidney transplantation and in other case, it was given 6 hours prior.

The University of Iowa has developed a protocol aimed for the pediatric population. Additionally, an aHUS longitudinal study is currently underway by the Molecular Otolaryngology and Renal Research Laboratories lead by Dr. Richard Smith, that will follow up biomarkers to assess what happens to patients with aHUS over time. This data-gathering is mostly because eculizumab has changed the survival curve and it is important to know the long-term outcomes.

Unfortunately, there is no data in regards to treatment withdrawal, but it is clear that single doses of eculizumab are ineffective and discontinuing the medication is associated with risk of recurrence in the first 3 months, hence treatment should be life-long. In regards to maintenance therapy, it has been reported that although tacrolimus and cyclosporine are associated with TMA (data is conflicting), tacrolimus is the first choice due to lower rates of TMA. Additionally, plasma exchange was also reported to be effective in some patients prior to the introduction of eculizumab as reported by Zuber et al. Furthermore, liver- kidney transplantation could be a potential cure for aHUS as the authors concluded in this paper. Also, it’s important to point out that patients require meningococcal vaccination prior to eculizumab administration

Zuber et al. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012 Nov;8(11);543-57

Eculizumab is expensive. I checked different sources for costs; a 300-mg vial costs around $7,500; consider the fact that this drug needs to be given life-long on a bi-weekly or monthly basis. Some sources consider it the most expensive drug in the world. Finally, eculizumab has protected rights until 2017 and until then, biosimilars would have the potential to reduce treatment costs. In conclusion, given the rarity of this disease it would be difficult to have a large randomized control trial, but given the available evidence, it appears to be effective in preventing the recurrence of the disease after transplantation.
(A warm thank you to Dr. Smith, Dr. Haririan and Dr. Thomas for their support and guidance)

What is the expected kidney function of a patient after donating a kidney?

A 31 year-old healthy male donated his kidney to his mother who had IgA nephropathy. Prior to donation, his creatinine was 1.08 mg/dl. One year after donation, his creatinine is 1.59 mg/dL. He was seeing in clinic and he is concerned about his high creatinine.
  What is the expected kidney function after donation? Kidney donation results in a 50% reduction in the kidney mass. However, there is an immediate hemodynamic compensation that increases the glomerular filtration rate in the remaining kidney. Studies have shown that there is a highly predictable increase in GFR of 20-40% within days resulting in a post-donation GFR of 60- 70% of baseline (reviewed by Mueller, Luyckx. JASN 2012). Subsequently, the remaining kidney undergoes some hypertrophy that will further compensate for the loss kidney.

 The most detailed paper describing the changes of renal function after kidney donation is from Rook et al. (AJT 2006), who evaluated 125 consecutive donors with iothalamate GFR clearance pre- and post-donation (around 2 months post-surgery). The average increase in creatinine was 35%. Older patients and those with greater BMI had a greater rise in creatinine. Another study reported the renal function of kidney donors 12 years post-transplant (Ibrahim et al. NEJM 2009). They noticed a drop ~24% in GFR at 12 years when compared to pre-donation. Reduced GFR was associated with aging, higher BMI and female sex. Longer time since donation is associated with the development of hypertension (~50%) and proteinuria (~35%) (Saran et al. NDT 1997).

  Our patient had a 51% increase in creatinine, which one may consider higher than expected. However, one must consider that creatinine is not a perfect marker of kidney function since it is significantly affected my muscle mass. This patient was muscular. When a creatinine clearance was calculated using CKD-EPI, his pre-donation eGFR was 95 ml/min and post-donation 63 ml/min – an expected drop in kidney function. A 24-hour urine collection confirmed this measurement. An iothalamate test would more reliably quantify his renal function but this test is not frequently performed. Equally important, his blood pressure has been well controlled and he does not have evidence of proteinuria.

 In summary, it is critical to monitor kidney donors with serum creatinine/eGFR (CKD-EPI), proteinuria and blood pressure levels. A drop in GFR ~35% is expected. More accurate GFR assessment may be considered with iothalamate in selected cases (e.g., older patients, patients with high or low BMI). After kidney donation, counseling patients about kidney risk factors is critical.

Midwest Transplant Symposium

Washington University at St Louis will be holding the inaugural Midwest Transplant Symposium on October 16th and 17th 2015.

This course is designed to be an in-depth review and update in kidney and pancreas transplant.
8.5 AMA PRA Category 1 Credits are available for this course.
Fellows and residents registration fee is $45 (plus $100 if CME credits are required).
For more information

OncoNephrology Conference 2015

One day symposium on OncoNephrology: Cancer, Chemotherapy and the Kidney

Where: Hofstra NSLIJ School of Medicine

When Sept 26th, 2015 from 7:30AM to 4PM 

The conference will highlight and review the latest happenings in OncoNephrology

This CME is free for all trainees including fellows

Talks and Speakers highlighted;

• AKI in Cancer Patients; Joseph Bonventre, Harvard Medical School
• Chemotherapy Toxicities: Mark Perazella, Yale University 
• Targeted Therapy and the Kidney: Kenar Jhaveri, Hofstra University 
• Hypercalcemia of Malignancy: Naveed Masani, Winthrop University 
• Anemia, CKD, ESKD and cancer: Steven Fishbane, Hofstra University 
• Renal Cancer, an update: Thomas Bradley, Hofstra University, NSLIJ Cancer Institute
• Paraneoplastic GN; Hitesh H Shah, Hofstra University 
• TMA: Bradley Dixon, Cincinnati Children Hospital 
• Post Kidney Transplant Cancers: Vinay Nair, Mt Sinai Medical Center 
• Paraproteinemias, an update: Gerald Appel, Columbia University Medical Center 
• Cases with the Onconephropathologist: Glen Markowitz, Columbia Medical Center 

Course directors: Kenar Jhaveri, Steven Fishbane and Thomas Bradley (Division of Nephrology and Hematology/Oncology at Hofstra NSLIJ School of Medicine)

Planning committee: Kenar Jhaveri, Steven Fishbane and Thomas Bradley, Hitesh H Shah, Pravin Singhal, Jyotsana Thakkar and Rimda Wanchoo (all from Division of Nephrology, Hofstra NSLIJ School of Medicine)

To Register: go here
Email kdj200@gmail.com for any questions re the conference.

This conference is endorsed by ISN, ASN, C-KIN and NKF

Keep cool and carry on...

Delayed graft function (DGF) after kidney transplant is associated with long-term allograft dysfunction. Niemann et al. (NEJM 2015;373:405) reported that therapeutic hypothermia reduced DGF (defined here as the requirement of dialysis in the recipient within 7 days after renal transplantation).

Study group enrolled 370 kidney donors after neurological determination of death (DNDDs), randomized to either normothermia (36.5 to 37.5 deg., n= 280) vs. mild hypothermia (34-35 deg. either by allowing to spontaneously reach the temperature, or by passive-cooling devices or forced-air systems, n=286). Incidence of DGF was significantly lower in hypothermia group (28.2% vs 39.2%, p=0.008), and study was terminated early.  

Therapeutic hypothermia (targeted temperature management) is an established intervention for outside-hospital cardiac arrest to protect neurological function.

In transplant field, in contrast, current organ procurement protocol (e.g. one from NATCO) has a stipulation that normal body temperature should be maintained in donors, frequently requiring active warming with warm blankets.

 What is the protective mechanism?  Authors discussed possible contribution of ischemia-reperfusion injury. Is this procedure applicable to other organs? Many questions arise and there is a nice open forum with NEJM group to discuss these (til August 7^th EDT).

Naoka Murakami, MD PhD