With the widespread use of new potent immunosuppressive agents, the incidence of acute rejection and acute graft failure has decreased significantly, and the incidence of acute rejection 6 months after transplantation has decreased from 50%-60% in the past to 15%-20% at present. However, the long-term survival rate of transplanted kidneys has not been significantly improved, and the reason for this may be related to insufficient long-term immunosuppression. In order to avoid the toxic side effects of cyclosporine (CsA), tacrolimus (FK506) and morte-macrolimus (primaquine), it is becoming more and more common for renal transplant recipients to reduce or discontinue their postoperative maintenance immunosuppressive drugs, and the individualized application of immunosuppressive drugs to maintain long-term immunosuppression while minimizing toxic side effects has become a hot topic of research in the transplantation community. Currently, the doses of primaquine, CsA and FK506 are usually adjusted by monitoring their blood levels to find a balance between immunosuppressive effects and toxicity, but these practices are often based on clinical experience and lack strict quantitative indicators. In a recent study, the National Institute of Nephrology, Nanjing General Hospital, Nanjing Military Region, used different doses of primaquine to evaluate the effect of transplanted kidney biopsy on the long-term survival of the transplanted kidney from pathological and immunopathological aspects. The results showed that after 1 year, the dose of primaquine was reduced in 48 patients with severe diarrhea and 15 with leukopenia due to the side effects of the drug. 6 of these patients discontinued the drug due to severe pulmonary infections or insufficient funds. 6 patients who discontinued the drug lost their transplanted kidney due to chronic rejection of the transplanted kidney between 3 and 6 months after discontinuation of the drug. The incidence of acute rejection, chronic rejection and graft renal failure was significantly higher in the primaquine low dose (≤1.0g per day, n=27) and primaquine ultra low dose groups (≤0.5/d, n=15) than in the primaquine regular dose group (mean dose ≥1.5g per day, n=40). The rate of transplant kidney failure was significantly higher in the primaquine ultra-low dose group than in the conventional and low dose groups. In the past, we reported that a sufficient dose of primidone combined with low-dose tacrolimus and glucocorticoids is the ideal treatment regimen for renal transplant recipients, and this regimen has a good prospect of application because of its low nephrotoxicity as well as less adverse effects and strong immunosuppressive effects. Many studies have shown that primaquine combined with FK506 and glucocorticoids can effectively prevent acute rejection in renal transplant patients and improve patient and graft survival. Recent studies have shown that the main cause of transplant renal hypofunction and transplant renal failure is not cyclosporine or tacrolimus nephrotoxicity but remains transplant renal rejection. Adequate doses of primaquine (≥1.5 g/day) can reduce the incidence of acute rejection by 50%. In most adult kidney transplant recipients, the dose of 1.5-2.0 g/day can maintain the concentration of primaquine (MPA-AUC0-12h) at 35-40 mg.h/l, which can play a strong immunosuppressive effect and can effectively prevent the occurrence of acute rejection. Thus, as a safe and highly effective immunosuppressive agent, primaquine has become the basic drug for immunosuppressive regimens at present. However, in clinical practice, it is found that some kidney transplant recipients reduce the oral dose of the most basic immunosuppressant primaquine to the extreme 1 to 3 years after kidney transplantation in order to save financial costs, either because the kidney transplantation has been long and everything is normal, or because the patients cannot tolerate it and have complications such as obvious diarrhea or leukopenia, and even 2% to 13% of patients will stop using Snapdragon. Recent studies have found that long-term use of primaquine causes variation in hypoxanthine mononucleotide dehydrogenase (IMPDH) activity and has become a hot topic of international interest. It has been reported in the literature that long-term application of primaquine causes variation in hypoxanthine mononucleotide dehydrogenase activity, which may lead to insufficient immunosuppression to induce graft rejection. There was an 8-fold difference between the activity of stable renal transplantation and rejection, and IMPDH activity was significantly correlated with primaquine dose, but not with primaquine concentration. Therefore, the long-term maintenance use of primaquine is not a dose reduction, but rather an appropriate dose increase, otherwise the risk of transplant renal failure is exacerbated. The use of transplanted kidney biopsy to assess the clinical efficacy of primaquine after renal transplantation is more realistic and reliable. We found that six patients who discontinued primaquine with regular use of FK506 and hormones had graft renal failure due to chronic rejection of the transplanted kidney between 3 and 6 months after discontinuation of the drug, respectively. The incidence of acute rejection, chronic rejection, and graft failure was significantly higher in the primaquine low-dose and ultra-low-dose groups than in the primaquine conventional dose group. The rate of transplant kidney failure was significantly higher in the primaquine ultra low dose group than in the primaquine regular dose group and primaquine low dose group. This shows that adequate doses of primaquine are necessary to reduce acute and chronic rejection of transplanted kidneys and to improve the long-term survival rate of transplanted kidneys. Theoretically, the incidence of acute rejection is significantly reduced at a fixed dose of primaquine (>1.5/d), while below 1.0/d, the rate of transplanted kidney failure is significantly increased. Since chronic immunosuppression of the transplanted kidney is not achieved below a certain dose, it leads to chronic lesions of the transplanted kidney (chronic interstitial fibrosis, chronic tubular atrophy, arterial hyalinosis, focal segmental glomerulosclerosis, striated fibrosis, increased thylakoid matrix, paraglobular fibrosis, FK506 nephrotoxicity, and chronic transplant nephropathy), resulting in increased infiltrating cells in the transplanted kidney and increased IL-2R and HLA- DR antigen expression was increased. When serious adverse reactions occur during drug administration, timely primidone dose reduction or even discontinuation is necessary, but the risk of graft kidney loss is greater when the drug is discontinued for more than 2 weeks. Pathologically, chronic interstitial fibrosis, chronic tubular atrophy, arteriolar hyalinosis, focal segmental glomerulosclerosis, striated fibrosis, increased thylakoid matrix, paraglomerular fibrosis, FK506 nephrotoxicity and chronic transplant nephropathy are all important factors affecting long-term survival of the transplanted kidney. In this study, the scores and percentages of chronic interstitial fibrosis, chronic tubular atrophy, arteriolar hyalinosis, focal segmental glomerulosclerosis, striated fibrosis, increased thylakoid matrix, paraglomerular fibrosis, FK506 nephrotoxicity and chronic transplant kidney nephropathy were significantly higher in the primaquine reduced dose group (primaquine low dose and primaquine ultra low dose groups) than in the primaquine conventional dose group. This indicates that primaquine has an important role in preventing chronic lesions in transplanted kidneys. As seen from immunohistochemical staining, the tissue cell infiltration (CD4+, CD8+, CD68+, CD138+ cells) and expression of IL-2R and HLA-DR in transplanted kidneys were significantly higher in the primaquine low-dose and primaquine ultra low-dose groups than in the primaquine conventional dose group. Comparing the pathological changes of transplanted kidneys in patients with stable transplanted kidney function in the primaquine conventional dose group and primaquine low dose group, the same differences were found in the percentage of Banff chronic interstitial score, FK506 nephrotoxicity, arterial hyalinosis, thylakoid stroma, paraglomerular fibrosis, and glomerulosclerosis. Thus, a protective effect of primaquine on transplanted kidney tissue was also seen in the subgroup without acute rejection, suggesting that primaquine also has an effect on non-immune factors. Our results showed that the survival rate of transplanted kidneys was significantly lower in patients treated with primaquine than in those treated with regular doses of primaquine when the dose was reduced to below the lowest dose or discontinued 1 year after surgery. This minimum dose of primaquine 1.0 g/d, and continued reduction or discontinuation of primaquine may lead to an increased risk of graft failure. The long-term survival of the transplanted kidney was followed for 3-4 years with the conventional dose of FK506 combined with primaquine R1.5 g/d, HR=1.0, and a serious effect on long-term survival was found for both the low dose of FK506 combined with primaquine and the ultra low dose of primaquine (risk factors 1.52 and 1.78, respectively). In conclusion, withdrawal or discontinuation of primaquine at any time after renal transplantation is dangerous. In order to improve long-term survival, it is emphasized that adequate doses of primaquine should be maintained for a long time in post-transplant patients. Pathologic and immunopathologic studies of transplanted kidneys have shown that in patients with good renal function after transplantation, withdrawal of primaquine 1.0/d, even if the dose of FK506 and hormones remains unchanged after transplantation, leads to a significant increase in the risk of renal failure, and withdrawal to 0.5/d is even more dangerous, leading directly to an abrupt decline in renal function and loss of the transplanted kidney.