Renal Disease

End Stage Renal Disease
Short Summary

54-year-old obese male with end stage renal disease due to membranous nephropathy, has received 2 renal transplants in the past and is highly sensitized. He underwent coronary angiography for vessel CAD, and PTCAs and stanting were performed. His current treatment consists of multiple medications including mycophylate according to the instructions of his transplant nephrologist. His cardiologists sees no contraindication to transplantation.

Patient's Questions

1. What are the chances of a transplant from the medical side, when putting in the equation his medical and antibody status?

2. What are the chances of finding a cadaver transplant in the USA with his high antibody level?

3. Is there an institute in the USA that will accept him for transplant?

4. What is the expected waiting time for this patient?

 

Medical Background

54 years old
Diagnosis: End Stage Renal Disease
S/P 2 Renal Transplants
 

This gentleman suffers from end stage renal disease due to membranous nephropathy and has received two kidney transplants 'in the past, In 1989 (cadaver) and 2002 (living unrelated). He suffers from ischemic heart disease, and underwent coronary angiography in2002, when PTCA and stenting to intermediate CX was performed. He returned to hemodialysis in April 2007 because of chronic allograft nephropathy.

He has been well on hemodialysis. A year ago he began to suffer from acute coronary syndrome, and a cardiac scan revealed antero-lateral ischemia. Coronary angiography revealed restenosis of intermediate CX; . PTCA and stenting was performed. In addition, PTCA and stenting of distal RCA was performed. Since then he has been well and asymptomatic. He has been found to suffer from sleep apnea in a sleep laboratory , and recommended to use CPAP, but he doesn’t use the mask. Physical examination revealed an obese man, no edema. Weight 90.5 kg, height 166 cm, BMI 32.8. No other abnormalities. He dialysis 3 times a week for 4 hours via a right arm AV graft , using Sureflux 190E dialyzer (cellulose triacetate, 1.9m²). Heparin 7000U by pump, Ca 1.25 Na 140, bicarbonate 35. BP before dialysis 154/76, after dialysis 155/78, average weight gain 2.5 kg. Blood pump (Qb) 300ml/min.
 

Laboratory Tests (3/2008)
Urea138mg/dl, creatinine7.25 mg/dl, Ca 8.6 mg/d, P 6.7 mg/dl, Na 141 141 meq/l, K 5.1 meq/l, Alk. Phosp. 186, T.P. 7.2g/dl, albumin 3.7g/dl, Uric acid7.9mg/dl, AST 14, ALT 22, Total cholesterol 168mg/dl, LDL 133mg/dl, HDL 49mg/dl, TG 223mg/dI. Hb 11.9, Hct 32.5%. platelets 210,000, WBC 7400. PT 100%, INR 1.0, PTT 31.6 secs, HbA1c 5.7%. HbSAg: Neg, HbSAb:Neg, HCVAb:Neg, HIV:Neg.
CMV IgG: Positive.
Allergies: none known.
 

Chest Xray: (6/7): Increased interstitial marking bilaterally, atelectasis at left
base. No pulmonary infiltrate. Heart shadow enlarged, aorta calcified.
EKG (2/08): Sinus rhythm within normal limits.
Abdominal Ultrasound (02/07): Liver: fatty infiltration, Gall bladder normal, contains stone: bile ducts: normal. Spleen: normal. Pancreas: normal.

Contracted native kidneys; transplanted kidney in LLD 12.2cm in Length; retroperitoneum: normal. no lymphadenopathy.

Echocardiogram (11/07): Concentric LVH, normal aortic root and ascending aorta; normal LV,LA and RV size; normal LV systolic function with posterior wall hypokinesis; diastolic LV dysfunction: calcified mitral annulus, calcified aortic valve, mild aortic stenosis, (peak gradient 19mm). No pulmonary hypertension.

Dipyridamole Thalium SPECT cardiac Scan (5/07): Antero-lateral-infero ischemia, LVEF 50%.

Coronary angiogram (7/07): Distal .LAD 50-70%. Intermediate CX > 90%, RCA to PDA 100%, Dilatation and stanting to intermediate and RCA performed successfully.

Doppler pelvic arteries (12/07): Normal diameter and flow in right and left external iliac arteries. Atheromatous plaques in left external iliac artery, but no stenosis.

Doppler leg arteries (10/07): Common femoral, superficial femoral and popliteal bilaterally: normal flows. Posterior, tibial and anterior tibial : mild narrowing bilaterally.

Dental Report (07/07): Following dental treatment. No evidence of oral pathology.

Blood Group B+

HLA Typing (3/08)
HLA: A 3(- )J32(19) , B.35(-). 52{S), Bw4/6, C4(-),c {-}
DR 2 {}/11() DQW1 ()/3() DRw 52/
HLA DNA: A*(-) ,A*(-)
DRBl*:02/11
DRB3*(-) ,DRB3*(-), DRB4*(-) , DRB4*(-), DRB5*(-), DRBS*(-)
DQB1*0601/0301
PRA: 1/08: 87%
7/07: 94%
5/07: 92%.
 


 

Lung function test: (10/07)
Pre-BC
FVC: 2.29 (61%)
FEV1: 1.83 (60%)
FEV1/FVC: 0.80
FEF 25-75%: 1.73 (48%)
PEFR: 7.05 (89%)
FEF50%: 2.58 (61%)
Conclusion: Moderate restrictive disease, Normal lung volumes.
PPD (5/07): 0mm

Medications:
Derbepoietin 150mcg x 1/week IV
IV Venofer 100mg x 1/week
Calcium carbonate 600mg x 3/d
Vitamin B complex 1/d
Aspirin 100mg/d
Mycophenylate Mophetyl 250mg/d
Atorvastatin 40mg/d
Clopidrogel 75mg/d
Lercanidipine 10mg/d
Ramipril 5mg/d
Metoprolol 190mg/d

The patient has received 2 transplants in the past and is highly sensitized. He is obese. He underwent coronary angiography in July for 3 vessel CAD, and PTCAs and stanting were performed.
His cardiologists sees no contraindication to transplantation. He continues on mycophylate according to the instructions of his transplant nephrologist.

 

Expert's Opinion

1. What are the chances of a transplant from the medical side, when
putting in the equation his medical and antibody status?

Medically, this patient seems to be a high risk for kidney transplantation. We would clear this patient for transplantation. However, employing aggressive desensitization protocols (see below) might change the center-specific medical inclusion criteria significantly.

2. What are the chances of finding a cadaver transplant in the USA with his high antibody level?

If no living donors are available or the strength of preexisting antibody levels is too high the next option would be to attempt lowering antibodies while waiting on the deceased donor list. The goal of the desensitization protocol is to decrease alloantibodies enabling the patient to be transplanted.

To qualify for this protocol at our center a patient must have PRA > 50% (which he has) and have > 5 years of waiting time accrued in the US. Therefore, a patient living abroad this is unlikely to be an option at least in NY area. Please note, that wait-time in US vary significantly. For example, Florida has compared to New York a significantly shorter wait time.

3. Is there an institute in the USA that will accept him for transplant?

If your patient has the financial resources or is covered by insurance, the best way to receive a kidney form a living donor. In this scenario it would be possible to test donor specific antibodies (done by single antigen Luminex assay). Based on the type and strength of these antibodies one option might be to “desensitize” the patients. Again, if the donor specific antibodies (DSA) are too high this might not be
possible and more donors would need to be tested. There several strategies currently available and published to “desensitize” the patients if the strength of DSA are acceptable.

At the Transplant meeting last week in Boston a novel approach using C5 inhibitor eculizumab in the prevention of acute humoral rejection in highly sensitized patients was presented by Dr Stegall (Mayo Clinic, Rochester, MN) (see abstract below). In addition, Dr Robert A. Montgomery Johns Hopkins Univ. School of Medicine, Baltimore might be a good option. However, if done outside clinical trials the costs of these regimens will be significant.

4. What is the expected waiting time for this patient?
See answer#3

[2009][178] Prevention of Acute Humoral Rejection with C5 Inhibition.
Mark D. Stegall, Tayyab S. Diwan, Justin M. Burns, Patrick G. Dean, Lynn D. Cornell, Manish J. Gandhi,
Fernando G. Cosio, James M. Gloor. Transplantation Surgery, Mayo Clinic, Rochester, MN; Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Laboratory Medicine, Mayo Clinic, Rochester, MN

Positive crossmatch kidney transplant (Tx) recipients may develop increased donor specific antibodies (DSA) early post-Tx resulting in acute humoral rejection (AHR). In the current study we evaluated the efficacy of the C5 inhibitor eculizumab in the prevention of AHR.

Methods. All patients had a positive B cell flow crossmatch (BFXM) against their living donor including: an historical control group (transplanted between Jan. 05 and Jan. 07; n=70) and an eculizumab group (n=3 with enrollment ongoing). Management included: 1) pts with a BFXM >300 at baseline underwent pre-Tx plasmapheresis (PP) to achieve a BFXM <300 (MESF=18,000) prior to Tx and PP for 4-7 days post-Tx; 2) pts with a BFXM <300 received no PP pre-Tx, but did have PP post-Tx if BFXM became >300; and 3) immunosuppression with thymoglobulin induction and maintenance tacrolimus, MMF and prednisone. The Eculizumab group (n=3) received drug at time of Tx (1200mg IV), and then weekly (600mg) through week 4. If DSA levels remained >200 after 4 weeks of treatment, then eculizumab (1200mg Q2 weeks) was continued through week 9. Both Eculizumab and Control groups underwent protocol biopsy and DSA determinations on days 4, 7, 10 and 14, and AHR was diagnosed (Banff criteria). The 1o
end point was the incidence of AHR in the first month post-Tx.

Results. In the Control group, the incidence of AHR in the first month was 36% with 23/25 (92%) having a  BFXM>400 (MESF>34,000) at the time of diagnosis, defining this DSA level as “high risk”. In the Eculizumab group, 2 pts reached “High Risk” DSA levels, yet AHR was not found on biopsy and PP was not performed. Both biopsies were C4d+ indicating complement activation upstream to C5. One patient had persistently low DSA levels. In all 3 pts, serum creatinine remained at nadir and electron microscopy was normal. Complement inhibition was achieved in all eculizumab pts and treatment appeared to be well tolerated.

Conclusion. Eculizumab treatment prevents AHR and may eliminate the need for post-Tx PP. This study shows that terminal complement activation is critical for development of AHR.

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