Efficacy and Safety of Telitacicept in Posttransplant Recurrent IgA Nephropathy

Written by Akshaya Jayachandran, DM

For many years, IgA deposits detected in a kidney allograft have often been viewed as relatively innocuous, particularly when found incidentally on protocol biopsies without accompanying proteinuria or graft dysfunction. Yet, as our understanding of IgA nephropathy evolves, and as targeted therapies begin to emerge, it is worth asking whether that long-held assumption will continue to hold true. One of the most fascinating lessons transplantation has taught us about IgA nephropathy is that IgA deposition and IgA nephropathy are not necessarily the same thing.

When we perform protocol biopsies after kidney transplantation, we sometimes find mesangial IgA deposits in patients with completely normal urine findings, stable graft function, and no clinical evidence of disease. Some donor kidneys even arrive with latent IgA deposits that disappear after transplantation into recipients without IgAN. These observations fundamentally changed how we think about the disease. They suggest that the kidney is not the primary problem. It’s the victim. The disease resides in the recipient’s immune system. That distinction matters enormously for nephrologists. 

Because when we see IgA staining in a graft biopsy, the first question should be: What exactly are we looking at? Is this merely an IgA deposition? Clinically relevant recurrent disease? De novo IgA nephropathy? Or is it an incidental histologic finding that may never affect graft survival?

Those questions frame the entire discussion around post-transplant IgA disease.

IgA deposits after transplantation: not all roads lead to IgAN

In native kidneys, the diagnosis of IgA nephropathy feels relatively straightforward. We see dominant or codominant mesangial IgA deposits, correlate with proteinuria or hematuria, and fit the findings into the broader clinical syndrome. After transplantation, things become considerably messier. A protocol biopsy may reveal mesangial IgA deposition in an otherwise healthy graft. The patient may have no hematuria. No proteinuria. No decline in eGFR. Should that be called recurrent IgAN?

Many transplant nephrologists would say no. The recent review by Ong and Julian highlights an interesting survey finding: most renal pathologists considered IgA deposition alone sufficient for diagnosis, whereas most nephrologists wanted additional evidence such as proteinuria, hematuria, or histologic injury before labeling it recurrent IgAN.  

Several experts have proposed separating IgA disease from IgA nephropathy in the transplant setting. Pure IgA deposition without urinary abnormalities may simply represent “IgA disease,” whereas IgA deposition accompanied by proteinuria, hematuria, or progressive injury is more appropriately termed recurrent IgA nephropathy. That distinction may seem semantic, but it isn’t. Treatment decisions depend on it.

What transplantation taught us about the biology of IgAN

One of the most elegant observations in nephrology comes from transplantation.

If IgAN were solely a kidney disease, replacing the kidney should cure it. But, recurrence remains common. Conversely, kidneys containing latent IgA deposits often lose those deposits when transplanted into recipients who do not have IgAN. This is why recurrent IgAN should be viewed primarily as a systemic immune disorder manifesting in the transplanted kidney.

The central pathogenic process remains remarkably similar to native-kidney disease. Patients continue producing galactose-deficient IgA1 (Gd-IgA1). Autoantibodies develop against these abnormal IgA molecules. Immune complexes form in the circulation. Eventually those complexes deposit in the mesangium and trigger inflammation and complement activation. The famous four-hit hypothesis survives transplantation intact. The graft is simply the new target.

Why post-transplant IgAN is not identical to native-kidney IgAN

Although the pathogenic framework is similar, recurrent disease behaves differently.

First, immunosuppression modifies the phenotype. Microscopic hematuria, one of the classic hallmarks of native IgAN, is often absent after transplantation. Many patients are diagnosed only after developing proteinuria or graft dysfunction. Others are identified through surveillance biopsies before clinical manifestations emerge. Second, the disease spectrum is broader. Some patients have isolated deposits.Others develop aggressive crescentic lesions. Many fall somewhere in between.Third, the background environment is completely different. The transplanted kidney is exposed simultaneously to calcineurin inhibitor toxicity, chronic antibody-mediated injury, ischemia-reperfusion effects, donor-related pathology, viral infections, recurrent glomerular disease disentangling these processes can be challenging.

The clinical problem: recurrence is common and not benign

For years, recurrent IgAN was considered relatively harmless. That perception is changing. The newer literature consistently demonstrates that recurrence is common and that its impact accumulates with time. Histologic recurrence can exceed 50% in protocol-biopsy cohorts, whereas clinically apparent recurrence is lower but still substantial. The important point is not simply recurrence. It is what recurrence does to the graft over the next decade. Multiple cohorts now show higher risks of graft dysfunction and graft loss once recurrent disease becomes established. Today, recurrent IgAN is increasingly viewed as a genuine threat to long-term graft survival rather than an interesting biopsy finding.

This brings us to the recent Kidney International Reports study evaluating telitacicept in recurrent IgAN after transplantation.  

For years, treatment of recurrent IgAN has largely been extrapolated from native disease. We optimized RAAS blockade and modified  immunosuppression.  Occasionally used steroids or rituximab. Yet none of these approaches convincingly altered the underlying biology. Telitacicept is different. It directly targets BAFF and APRIL, two critical signals involved in B-cell survival, plasma-cell maturation, and production of pathogenic antibodies. These pathways sit upstream of galactose-deficient IgA1 generation and immune-complex formation. In other words, the drug attempts to intervene at the source rather than merely cleaning up the consequences. 

The study at a glance

This was a prospective, single-center, single-arm cohort study from Shanghai including 25 kidney transplant recipients with biopsy-proven recurrent IgAN and persistent proteinuria despite standard management. Twenty-two completed follow-up. All patients continued baseline transplant immunosuppression while receiving telitacicept. The average patient was nearly seven years post-transplant. Median proteinuria exceeded 1.3 g/day, and many already had significant chronic lesions on biopsy.  

What did they find?

The headline result? Proteinuria fell substantially. By week 28, 24-hour urinary protein fell by approximately 52%. UACR fell by approximately 63%. Nearly half achieved complete remission and more than half achieved partial remission. Equally important, kidney function remained stable. Serum creatinine and eGFR showed no evidence of deterioration during follow-up. There were no serious adverse effects.

Discussion: A Promising Signal, But long term outcomes?

At first glance, a 52% reduction in proteinuria over 28 weeks in a population with biopsy-proven recurrent IgAN is difficult to ignore. In a field where therapeutic options are largely borrowed from native-kidney IgAN and where recurrent disease continues to threaten long-term graft survival, any intervention producing this magnitude of antiproteinuric effect immediately attracts attention.The more important question, is whether telitacicept was truly responsible. That is where things become considerably more complicated.

The first issue is study design. This was a prospective single-arm cohort without a comparator group. There was no standard-of-care arm, and no randomization. Consequently, every observed improvement must be interpreted against the possibility of regression to the mean, spontaneous fluctuations in proteinuria, and the natural variability that characterizes recurrent IgAN. Patients with recurrent IgAN can demonstrate substantial variation over months even without major therapeutic interventions. In a controlled trial, this background variability is distributed between groups. In a single-arm study, it becomes impossible to quantify. The authors appropriately emphasize the reduction in proteinuria, but the absence of a control group prevents us from determining how much of that reduction reflects a true drug effect.

Secondly, these were not treatment-naïve patients. Participants were receiving maintenance tacrolimus, mycophenolate, and corticosteroids. Nearly half were already on ARB therapy, while some had previously received targeted-release budesonide. The study therefore evaluates telitacicept as an add-on intervention superimposed upon a heterogeneous therapeutic background. This mirrors real-world practice but complicates interpretation. Would the same response have occurred in patients receiving optimized RAAS blockade, SGLT2 inhibition, and contemporary supportive care? We simply do not know. Notably, none of the patients were receiving SGLT2 inhibitors or endothelin receptor antagonists, therapies increasingly being added to modern proteinuric kidney disease management. 

The third issue is duration. 28 weeks is sufficient to detect changes in proteinuria. But it is not sufficient to establish preservation of graft survival. Recurrent IgAN is fundamentally a chronic disease measured in years rather than months. The major clinical concern is progressive graft dysfunction and eventual graft loss. The study demonstrated stable serum creatinine and eGFR, but expecting meaningful changes in kidney function over six months is unrealistic. As a result, the study answers a surrogate endpoint question rather than a clinically definitive one. 

The fourth issue relates to pathology. Every participant had biopsy-proven recurrent disease, which strengthens diagnostic certainty. Yet repeat biopsies were not performed after treatment. This is a missed opportunity. One of the most intriguing aspects of recurrent IgAN is the disconnect between histologic activity and clinical manifestations. We therefore do not know whether telitacicept merely reduced proteinuria or whether it actually altered mesangial inflammation, endocapillary hypercellularity, complement activation, or chronic injury progression.

To the authors' credit, they attempted to address the mechanism through biomarker analysis. Reductions in circulating galactose-deficient IgA1 and ASGPR levels are biologically plausible and consistent with the known mechanism of BAFF/APRIL inhibition. This is perhaps the most compelling aspect of the study. For the first time in recurrent disease, we see evidence that manipulating a pathway central to the four-hit hypothesis may influence both biomarkers and clinical outcomes. The challenge, however, is that biomarker movement alone cannot establish causality. We still do not know whether reductions in circulating Gd-IgA1 directly translate into improved long-term graft outcomes. 

The safety findings also deserve a more cautious interpretation. No severe treatment-related adverse events were observed, which is reassuring. However, only to patients completed follow-up. Such a sample is incapable of detecting uncommon but important complications. This is particularly relevant because transplant recipients already receive multiple immunosuppressive agents. Adding another therapy targeting B-cell survival pathways raises obvious concerns regarding infection risk, malignancy surveillance, and long-term immune competence. 

The most interesting aspect of this paper is not the drug itself but what the study represents. For decades, recurrent IgAN has existed in a therapeutic orphan state. Most advances in native-kidney IgAN never reached transplantation. The field largely relied on supportive care. Rather than treating recurrent IgAN as an unavoidable consequence of transplantation, the investigators have approached it as a biologically targetable disease process. The real question is whether BAFF/APRIL inhibition deserves testing in a randomized controlled trial specifically designed for recurrent IgAN. Based on these data, the answer is yes. The study provides a strong signal. What it does not provide is proof. And in recurrent IgAN, where promising observational findings have repeatedly failed to transform clinical practice, that distinction matters.

The telitacicept study offers a glimpse of what post-transplant IgAN management may look like in the next decade. It means less empirical immunosuppression and more pathway-directed treatment. And perhaps the most important lesson from all these studies is this: The presence of IgA in a graft biopsy is not the diagnosis. It is the beginning of the diagnostic conversation. Understanding whether IgA represents innocent deposition, recurrent disease, or progressive immune injury remains one of the most important challenges in modern transplant nephrology.