Humoral rejection: What the pathologist should know

Excellent discussion of the topic but I wonder if C4d or for that matter humoral rejection is important in a live related renal transplant setting with related donors, very low PRAs and majority of transplants being first transplants. This is the situation we are confronted with. We have been doing C4d since last 4 years but only found 2 positive cases, those also showing only focal positivity. So what is others experience. Please comment on this important question.
Thanks
DR Mubarak, Karachi, Pakistan

Without knowing the number of transplantations performed at your institution during the last four years I assume that two C4d positive cases reflect a very low rate of C4d positives. That’s what I would expect for your low risk population (if we are talking about genetically related donors/recipients).
The isolated finding of C4d, especially if it is only focal staining, is not a proof of clinically relevant humoral rejection. This seems to apply for any kind of kidney transplant, regardless the immunological risk. “C4d only” therefore is no indication for immediate therapy.
In a given individual case it is generally impossible to predict what positive C4d staining means unless there are additional risk factors present that increase the likelihood of a serious rejection. The most important among those are: Declining renal function, capillary lesions (capillaritis, glomerulitis, glomerulopathy).
If C4d is found in a protocol biopsy (of a graft with stable renal function) and no morphological lesions are present, I would check the patient for donor specific antibodies (not just PRA) and repeat the whole procedure after 3-6 months (in case of dysfunction, earlier) in order to get an estimate of the dynamics of the putative humoral response.
I can’t tell you how efficient this strategy is in preventing graft losses since we do not have protocol biopsies. But I think it might be an efficient approach for avoiding overtreatment of patients and also would increase our knowledge of the condition.

Thank you very much for detailed rejoinder to my question. I think we have got the answer and you are right, all our patients are genetically related. Majority are siblings, rest are parents or children with few spouses. Since last one year, we are doing 12 transplants a week, quite large number.
Thanks again for clarifying many points.
Dr M Mubarak