#155 - Chris Sonnenday, M.D.: The history, challenges, and gift of organ transplantation

Sonnenday recounts Jeff and Tina Webster, whose 21-year-old son Aaron died in a Jeep rollover: without hesitation they donated every organ, eventually got to know all the recipients, and one recipient has a tattoo of Aaron on his arm. He also describes Attia's own experience — a childhood friend whose mother donated every organ including split liver, corneas, and skin — as the kind of story that illustrates the scope of one donation's impact. More than 100,000 people are currently on transplant waiting lists in the US; fewer than 40,000 transplants are performed annually; the gap grows each year.

Sonnenday traces the mechanistic evolution: first high-dose steroids and azathioprine were used to blunt the immune response broadly; total body irradiation was attempted at Brigham and Women's (Francis Moore's era). None selectively addressed cellular rejection until cyclosporine revealed that interfering with the T-cell receptor downstream cascade — specifically the calcineurine-immunophyllin complex and IL-2 secretion — was the key. Tacrolimus (FK506) arrived as a more potent successor with a cleaner nephrotoxicity profile in the right dosing range. The field continues to refine combinations to minimize cumulative toxicity while preventing both acute and chronic rejection.

Sonnenday traces the intellectual history: the first insight that tissue incompatibility was immunologic came from skin graft experiments where a second graft from the same donor was rejected faster — suggesting the immune system had been primed (same principle as a vaccine's second-hit response). The question of whether rejection was humoral (circulating antibodies) or cellular took decades to resolve. It turned out to be both: hyperacute rejection is antibody-mediated, similar to ABO blood type incompatibility (and manageable by crossmatch testing); acute and chronic rejection is T-cell-mediated cellular rejection, requiring calcineurin inhibitors to prevent.

Sonnenday explains the history of preservation solutions: the principle of flushing the organ with a fortified electrolyte solution (Wisconsin solution and its predecessors) to mitigate ischemic cellular processes has not fundamentally changed since the 1960s–70s. What has changed is the recognition that 'machine perfusion' — keeping the organ on a perfusion circuit rather than static cold storage — is showing promise in extending tolerable ischemic times and allowing assessment of organ viability before implantation. This is especially important for DCD organs, which have had more ischemic injury before procurement.

Attia frames kidney function as the 'glider altitude' problem: if you want to cross a 300-foot chasm instead of a 200-foot chasm, you need to start higher. He calculated that a GFR of 95 in midlife declining at 1 mL/min/year naturally, plus a 'too high' blood pressure adding an incremental 1 mL/min/year of decline, reaches dialysis territory well within a 90-year lifespan. The 100,000-person US transplant waitlist with roughly 4-fold more on dialysis and 10-fold more with progressive CKD represents a public health crisis that will only intensify as the pre-diabetes and metabolic syndrome epidemic ages into renal failure.

Sonnenday describes the Hopkins M&M as the most intense hour of the week outside the OR. The key cultural feature: former chair John Cameron always moderated and always led with his own complications first. The story Attia tells illustrates the principle from the other direction: Sonnenday caught a missed compartment syndrome on a patient already being discharged, took the patient to the OR, saved his leg — and then presented the case at M&M as though it were his own miss, never revealing the circumstances that led to the near-miss. The effect on junior residents like Attia was profound: it modeled a standard of accountability that had nothing to do with blame.

Attia recalls a 21-year-old who took a bottle of acetaminophen after a breakup and was lucid enough to understand her situation — INR and LFTs through the roof — while knowing she would die without a transplant. She was listed and transplanted. Sonnenday frames the ethical calculus: who among us hasn't done a dumb thing at 21, and the transplant community's general approach is to give such patients the benefit of the doubt and address mental health afterwards rather than using the circumstances of the overdose as a gatekeeping criterion.

Dr. Sonnenday explains the two factors compounding each other: first, deceased-donor kidneys suffer literal nephron loss from ischemia-reperfusion injury; second, that same injury cascade is a priming event for the immune system, making those kidneys more prone to rejection and typically requiring more aggressive immunosuppression. Living-donor kidneys, even with mismatched HLA antigens, sidestep both problems. The implication is that every transplant candidate should be strongly counseled to explore living donation before waiting for a deceased-donor match, and that paired kidney exchange networks (algorithms pioneered partly by colleagues Dory Segev and Summer Gentry) can widen the compatible-donor pool for those whose intended donor is blood-type or HLA incompatible.

Sonnenday notes the outcome was not simply fewer transplants: patients who already had cirrhosis but cleared the virus on DAAs showed unexpected hepatic recompensation — their livers partially repaired, and many who had been on a certain trajectory toward transplant never needed one. The contrast with NASH is stark: with NASH the driver is metabolic syndrome and obesity, and we have no DAA-equivalent to interrupt the fibrosis cascade before it reaches cirrhosis.

Sonnenday observes that the NASH transplant population now looks more like the kidney transplant population — they carry cardiovascular comorbidities that threaten long-term survival as much as their liver disease and immunosuppression do. Alcohol-related liver disease is notable for its increasingly young presentation: patients in their 20s and 30s destroying their liver, analogous to the opioid crisis in terms of underlying behavioral disease but treated less urgently by medicine and society because alcohol is freely available and its toxicity is chronic rather than acutely binary.

Sonnenday explains the apnea test: mechanical ventilation is briefly suspended; failure to generate any spontaneous respiratory effort, combined with other criteria (absent brainstem reflexes, hemodynamic stability, absence of confounding metabolic conditions), confirms brain death. He also emphasizes the ethical architecture: the treating ICU team has no involvement with the transplant team; the organ procurement organization (OPO) is engaged only after brain death is confirmed and the family has indicated their wishes. For DCD, withdrawal of care happens entirely before any transplant machinery is involved, and a provider with no transplant affiliation declares death.

Sonnenday notes a practical side effect: patients at the top of the national liver list (most severely ill by MELD score) now get transplanted very rapidly because they draw from a national pool; the challenge shifts to the 'medium sick' tier who now compete with sicker patients across the country. The underlying solution is expanding the donor pool through increased deceased-donor registration and living-donor programs.

Attia's hypothesis: the core reason no machine can replicate the liver is the regulation of blood glucose. Gluconeogenesis and glycogen storage require real-time adjustment at the milligram level with seconds of latency tolerance — a computational and biochemical complexity that current mechanical or cell-based systems cannot match. This also explains why acute liver failure (e.g., acetaminophen overdose) is so lethal in a narrow time window: the patient is cognitively intact enough to understand their prognosis while coagulation and synthetic function collapse simultaneously.

Sonnenday describes performing a laparoscopic donor nephrectomy and shipping the kidney to another institution, while a kidney from a donor at that institution was shipped back for their two recipients — the donor operations and recipient operations were completely dissociated in space and time. The complexity introduced is the quality and compatibility tradeoff: a swap might exchange a younger, healthier living-donor kidney for an older one, or create an immunologic situation requiring more immunosuppression. The algorithms price in these differences to maximize net benefit across the entire chain.