Kidney transplant outcomes in patients with complement dysregulation

Abstract

BACKGROUND

Complement dysregulation is a key mechanism underlying atypical hemolytic uremic syndrome and complement-mediated thrombotic microangiopathy in kidney transplantation, and is associated with post-transplant recurrence, graft dysfunction, and graft loss. Although Western cohort data are well established, integrated transplant outcome data combining genetic analysis, anti-factor H (AFH) antibody profiling, and individualized therapy from Indian and other South Asian populations remain limited, despite a distinct biologic profile in this region.

AIM

To evaluate clinical characteristics, complement biologic profile, post-transplant recurrence, and graft outcomes in kidney transplant recipients with complement dysregulation managed at a tertiary transplant center in Central India, with particular emphasis on genotype-phenotype correlation and outcomes in a resource-constrained setting.

METHODS

This single-center retrospective cohort study included kidney transplant recipients with evidence of complement dysregulation identified from January 2018 to March 2025 at a tertiary transplant center in Central India. Complement dysregulation was defined as the presence of a pathogenic or likely pathogenic complement gene variant, AFH antibody positivity, or both. Genetic testing was performed using multiplex ligation-dependent probe amplification and/or clinical exome sequencing covering the alternative complement pathway gene panel, and AFH antibodies were measured using enzyme-linked immunosorbent assay. All patients underwent comprehensive evaluation including hematological, biochemical, and complement (C3, C4) profiling, with kidney biopsy when clinically feasible. The primary outcome was post-transplant recurrence of thrombotic microangiopathy; secondary outcomes included graft loss, patient survival, renal function, and treatment response. Median post-transplant follow-up was approximately 12 months.

RESULTS

Of the 335 patients evaluated for complement abnormalities, 136 had complement dysregulation, of whom 38 underwent kidney transplantation and constituted the study cohort. Mean age was 36.3 ± 9.3 years, 84.2% were male, and 97.4% had hypertension; 73.7% were on maintenance hemodialysis at diagnosis. Complement genetic abnormalities were identified in 34/38 recipients (89.5%), with CFHR1-CFHR3 structural variants predominating (78.9%) and complement factor H abnormalities in 18.4%; no pathogenic variants were detected in CFI, C3, CD46, THBD, or DGKE. AFH antibodies were detected in 15 patients (39.5%), with 11 having concomitant genetic abnormalities. Pre-transplant immunomodulation with plasma exchange and rituximab reduced mean AFH antibody levels from 179.9 AU/mL to 59.7 AU/mL (approximately 67% reduction). Post-transplant recurrence occurred in 7/38 recipients (18.4%), all biopsy-confirmed, donor-specific antibody and C4d-negative, and clustered within 1-3 weeks of transplantation; recurrence occurred exclusively in patients with complement genetic abnormalities, and not in those with isolated AFH antibody positivity. All 7 recipients with recurrence maintained functioning grafts after disease-directed therapy. Overall patient survival was 94.7%; two deaths (5.3%) were attributable to severe infections, and one graft loss followed invasive mucormycosis unrelated to recurrent disease.

CONCLUSION

In this Indian transplant cohort with complement dysregulation, CFHR1-CFHR3 structural variants and AFH antibody positivity defined the predominant biologic substrate, post-transplant recurrence clustered within the early weeks after transplantation, and disease-directed therapy with plasma exchange, rituximab, and selective eculizumab achieved durable graft preservation despite limited access to long-term complement inhibition. Comprehensive pre-transplant complement evaluation and biologic risk stratification are essential for safe transplantation in complement-mediated kidney disease, particularly in resource-limited settings.

Key Words: Atypical hemolytic uremic syndrome; Thrombotic microangiopathy; Kidney transplantation; Complement dysregulation; Anti-factor H antibody; CFHR1-CFHR3

Core Tip: Complement dysregulation is an important but underrecognized determinant of post-transplant thrombotic microangiopathy. In this retrospective cohort of 38 kidney transplant recipients with complement dysregulation, CFHR1-CFHR3 structural variants predominated, anti-factor H antibodies were frequent, and recurrence occurred in 18.4%. All recurrences developed within the first 1-3 weeks post-transplant and were confined to recipients with complement genetic abnormalities. All episodes were successfully controlled with individualized therapy. Overall patient survival was 94.7%. These findings support systematic complement evaluation, biologic risk stratification, and early targeted intervention to optimize transplant selection, reduce recurrence risk, and improve post-transplant graft outcomes in complement-mediated kidney disease.

INTRODUCTION

Thrombotic microangiopathy (TMA) is a major cause of kidney injury and allograft dysfunction in kidney transplantation[1,2]. In the transplant setting, TMA may occur either as recurrent disease in patients with underlying complement dysregulation or as de novo post-transplant TMA triggered by calcineurin inhibitor exposure, ischemia-reperfusion injury, infection, antibody-mediated rejection, or other endothelial stressors[3,4]. Distinguishing complement-mediated TMA, classically presenting as atypical hemolytic uremic syndrome (aHUS), from secondary forms is critical, as complement-mediated disease carries a substantially higher risk of post-transplant recurrence, graft dysfunction and graft loss, and requires disease-specific management[5-7]. Complement pathway abnormalities have also been identified in a subset of patients initially classified as secondary TMA, suggesting that complement dysregulation may be underrecognized in the post-transplant setting[8,9].

Complement factor H (FH) is the principal soluble regulator of the alternative complement pathway[10]. It limits complement amplification by accelerating decay of the alternative pathway C3 convertase (C3bBb) and by acting as a cofactor for factor I-mediated cleavage of C3b[11]. Through these mechanisms, FH regulates complement activity both in the fluid phase and on host cell surfaces[12]. In the fluid phase, FH destabilizes inactivated C3b by displacing Bb from factor B and promotes conversion of C3b to inactive iC3b[10,11]. At the cell surface, FH binds host-associated ligands, including sialic acids, glycosaminoglycans, heparin-like molecules, and C3d, thereby directing complement regulation to self-surfaces and protecting endothelial and epithelial tissues from unintended complement-mediated injury[13]. Dysregulation of FH-mediated complement control at the vascular endothelial surface represents a central pathogenic mechanism in aHUS and a key determinant of complement-mediated TMA, post-transplant recurrence, and graft injury[5,14].

FH dysfunction may arise from either genetic abnormalities involving complement factor H (CFH) or CFH-related genes (CFHR), or from acquired autoantibodies directed against FH, both of which impair physiologic control of the alternative pathway[15]. The CFH-CFHR gene family, located within the regulators of complement activation region on chromosome 1q32, comprises CFH and CFHR1-CFHR5[16]. Due to extensive sequence homology within this region, the locus is prone to non-allelic homologous recombination, leading to deletions, duplications, hybrid genes, and other structural rearrangements implicated in complement-mediated diseases, including aHUS[17]. Abnormalities involving the CFHR1-CFHR3 region are of particular relevance[18]. Unlike FH, CFHR proteins lack the full regulatory domains required for cofactor and decay-accelerating activity and may compete with FH for binding to C3b or other ligands, thereby promoting complement activation[18,19]. CFHR1, CFHR2, and CFHR5 have been described as competitive antagonists of FH, whereas CFHR4 and CFHR5 may facilitate formation of the alternative pathway C3 convertase[19].

An additional mechanism of complement dysregulation is the development of anti-FH antibodies (AFH), which interfere with FH regulatory activity and result in uncontrolled alternative pathway activation[20]. These autoantibodies are more commonly associated with aHUS than with C3 glomerulopathy, and their prevalence varies geographically, with higher frequencies reported in South Asian cohorts[21]. AFH antibodies frequently coexist with structural abnormalities involving CFHR1/CFHR3, suggesting an interaction between inherited complement susceptibility and acquired immune dysregulation[22]. Accordingly, complement-mediated TMA is increasingly recognized as a spectrum of combined genetic and acquired mechanisms rather than a purely monogenic disorder[18,20].

Management of complement-mediated TMA has evolved with improved understanding of alternative pathway dysregulation[6]. Terminal complement blockade with anti-C5 monoclonal antibodies, including eculizumab and ravulizumab, has significantly improved hematologic and renal outcomes[23]. However, access to complement inhibitors remains limited in many regions, and plasma exchange-based immunomodulatory strategies remain important in clinical practice[6,21].

Most transplant experience in complement-mediated kidney disease is derived from Western cohorts, where pathogenic CFH variants account for the majority of cases and are associated with recurrence rates of 40%-70% in the absence of complement inhibition[5,10,22]. In contrast, the genetic and serologic profile in Indian and other South Asian populations appears distinct, with a greater contribution from CFHR1-CFHR3 structural rearrangements and AFH antibody positivity[18,21]. Despite this, integrated transplant outcome data combining genetic analysis, AFH antibody profiling, and individualized therapy from this region remain limited.

Given the heterogeneity of complement-mediated TMA, variability in recurrence risk based on underlying complement abnormalities, and the challenges of management in resource-limited settings, additional data are required to inform transplant decision-making in biologically defined patient populations[7,8]. In particular, outcomes in patients with CFH/CFHR-related abnormalities or AFH antibody positivity remain incompletely characterized[7,9].

The present study therefore evaluated kidney transplant outcomes in patients with complement pathway abnormalities, with specific emphasis on clinical phenotype, recurrence of TMA, and graft outcomes in the context of complement gene mutations and regulatory dysfunction.

MATERIALS AND METHODS

Study design and study population

This was a single-center retrospective cohort study at a tertiary kidney transplant center in Central India, from January 2018 to March 2025. During this period, 335 patients underwent evaluation for complement abnormalities based on clinical suspicion of complement-mediated kidney disease. Evaluation was undertaken in patients presenting with TMA or suspected aHUS, and in young individuals with severe or malignant hypertension and unexplained kidney dysfunction. Complement dysregulation was defined as the presence of a pathogenic or likely pathogenic complement gene variant, AFH antibody positivity, or both, in the appropriate clinical context. Of the 335 patients evaluated, 136 met this definition, and 38 underwent kidney transplantation, forming the final analytic cohort. The study was conducted in accordance with the Declaration of Helsinki and was reviewed and approved by the SKCC Institutional Ethics Committee, SS Multispecialty Hospital, Nagpur, India (Approval No. ECR/1725/Inst/MH/2022). Reporting followed STROBE guidelines.

Diagnostic evaluation of TMA and complement-mediated disease

All patients were evaluated for TMA using clinical, laboratory, and histopathological criteria. TMA was defined by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury or graft dysfunction, supported by elevated lactate dehydrogenase, reduced haptoglobin, and schistocytes on peripheral smear. Baseline serum C3 and C4 levels were measured to assess complement pathway activity.

A native kidney biopsy was performed where clinically feasible. Biopsies were assessed for features of TMA, including endothelial swelling, mesangiolysis, fibrin thrombi in glomerular capillaries or arterioles, and arteriolar intimal edema. In patients on long-term maintenance dialysis, native biopsy was not performed given limited diagnostic yield and procedural risk in end-stage kidneys. In this group, diagnosis was based on the clinical phenotype, complement genetic testing, AFH antibody profiling, and exclusion of alternative causes. Graft biopsy was performed whenever post-transplant TMA was suspected.

Alternative causes of TMA were excluded, including malignant hypertension, infection-associated TMA, drug-induced TMA, pregnancy-associated TMA, and antiphospholipid antibody syndrome. In transplant recipients, evaluation additionally included donor-specific antibody testing, C4d staining on graft biopsy to exclude antibody-mediated rejection, tacrolimus trough levels with histological assessment for calcineurin inhibitor toxicity, and screening for active infection.

Complement testing

Genetic testing was performed using multiplex ligation-dependent probe amplification and/or clinical exome sequencing at an accredited laboratory. Multiplex ligation-dependent probe amplification was carried out using a commercially available kit to detect copy number variations within the CFH-CFHR region, which is prone to deletions, duplications, and rearrangements due to high sequence homology. Clinical exome sequencing was performed on an Illumina platform with mean coverage greater than 100 ×. The complement gene panel included CFH, CFI, C3, CFB, CD46 (MCP), CFHR1-CFHR5, THBD, and DGKE.

Variants were classified according to American College of Medical Genetics and Genomics guidelines as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign. Only pathogenic and likely pathogenic variants were considered disease-associated. AFH antibodies were measured by enzyme-linked immunosorbent assay (VIDITEST, Vidia Ltd., Czech Republic), detecting immunoglobulin G antibodies against complement FH. Levels ≥ 100 AU/mL were considered positive. Serial measurements were obtained in selected patients to assess antibody kinetics during plasma exchange or immunosuppressive therapy.

In patients on long-term dialysis, AFH antibody titers were interpreted with caution. Prolonged dialysis vintage, prior plasma therapy, or earlier immunosuppression may reduce circulating antibody levels; a negative titer does not exclude prior antibody-mediated complement dysregulation. Patients with complement gene variants and negative AFH titers were not considered low risk based on seronegativity alone, particularly when dialysis duration was prolonged or the clinical phenotype suggested complement-mediated TMA.

Transplantation and immunosuppressive management

All recipients underwent standard pre-transplant evaluation, including ABO compatibility, human leukocyte antigen typing, complement-dependent cytotoxicity crossmatch, flow cytometry crossmatch, and donor-specific antibody assessment. Both living and deceased donor transplants were included. Induction therapy consisted of anti-thymocyte globulin or basiliximab based on immunologic risk. Maintenance immunosuppression included tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus trough levels were maintained at 8-10 ng/mL in the early post-transplant period and 5-7 ng/mL during maintenance, with regular monitoring.

Disease-directed therapy was tailored to the biologic profile and clinical severity. Plasma exchange was performed using 1.5 plasma volumes per session with fresh frozen plasma replacement on alternate days, with the number of sessions guided by clinical response and serial AFH antibody titers where relevant. Rituximab was administered at 500 mg per dose to deplete B cells and suppress AFH antibody production; this approach was also applied to seronegative patients with prolonged dialysis vintage, given the possibility of falsely low antibody titers.

Eculizumab became available in India during the latter part of the study period and was offered to biologically high-risk recipients, including those with CFH variants, persistent AFH antibody positivity, or prior recurrent disease. The standard regimen consisted of 900 mg weekly for 4 weeks, followed by 1200 mg every 2 weeks from week 5. However, cost (approximately ₹1 Lakh/US $1200 per 300 mg vial) and limited insurance coverage restricted uniform use. In selected high-risk recipients, a single 900 mg pre-transplant dose was administered alongside plasma exchange and rituximab, while post-transplant therapy was reserved for refractory recurrence. All patients receiving eculizumab were vaccinated against meningococcus at least two weeks prior to initiation.

Study outcomes

The primary outcome was recurrence of TMA after kidney transplantation. Recurrence was defined by reappearance of microangiopathic hemolytic anemia, thrombocytopenia, and rising serum creatinine, with graft biopsy demonstrating features of TMA. Antibody-mediated rejection (donor-specific antibody-negative, C4d-negative), calcineurin inhibitor toxicity, and active infection were excluded before confirming recurrence. Disease-directed therapy was initiated after biopsy confirmation.

Secondary outcomes included death-censored graft loss, patient survival, post-transplant renal function, and response to therapy. Renal function was assessed using serial serum creatinine and estimated glomerular filtration rate. Patients were followed from transplantation until last clinical contact or study end, with a median follow-up of approximately 12 months.

Statistical analyses

Statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, United States). Normality was assessed using the Shapiro-Wilk test. Continuous variables are presented as mean ± SD or median with interquartile range, as appropriate. Categorical variables are expressed as n (%). Given the descriptive design and modest sample size, inferential statistical comparisons were not performed.

RESULTS

The cohort flow from initial complement evaluation to the final transplant analysis is shown in Figure 1. Of the 335 patients evaluated for complement abnormalities, 136 met criteria for complement dysregulation. Of these, 38 underwent kidney transplantation during the study period and formed the analytic cohort.

Figure 1 Cohort flow and post-transplant outcomes in patients with complement dysregulation. AFH: Anti-factor H.

Baseline clinical characteristics

Baseline demographic and clinical features are presented in Table 1. The mean age was 36.3 ± 9.3 years (median 33; range 22-58), with a marked male predominance (84.2%). Hypertension was present in 97.4% of patients. At the time complement dysregulation was recognized, most patients had advanced kidney failure: 73.7% were on maintenance hemodialysis, 7.9% had stage V chronic kidney disease not yet on dialysis, and 7.9% presented with acute kidney injury, with biopsy-confirmed TMA in this last group. In 4 patients (10.5%), complement dysregulation was first identified after transplantation during evaluation for graft dysfunction or suspected recurrence. Baseline serum C3 was reduced (below 90 mg/dL) in 41.3% of patients (mean 92.4 ± 28.6 mg/dL), whereas serum C4 remained within the normal range (mean 29.7 ± 9.8 mg/dL). This pattern of low C3 with preserved C4 is in keeping with predominant alternative pathway activation.

Table 1 Baseline demographic and clinical characteristics of the study cohort, n (%).

Variable	Value
Age (years)
mean ± SD	36.3 ± 9.3
Median (IQR)	33.0 (30.3-43.8)
Range	22-58
Sex
Male	32 (84.2)
Female	6 (15.8)
Hypertension
Present	37 (97.4)
Absent	1 (2.6)
Diabetes status
Diabetes mellitus	1 (2.6)
Post-transplant diabetes mellitus (NODAT)	3 (7.9)
No diabetes	34 (89.5)
Clinical scenario at diagnosis of complement abnormality
CKD stage V on maintenance hemodialysis	28 (73.7)
Advanced CKD stage V not on dialysis	3 (7.9)
AKI	3 (7.9)
Diagnosed post-transplant	4 (10.5)
Median post-transplant follow-up (months)	12
Survival at last follow-up
Alive	36 (94.7)
Deceased	2 (5.3)

AKI: Acute kidney injury; CKD: Chronic kidney disease; IQR: Interquartile range; NODAT: New-onset diabetes after transplantation; SD: Standard deviation.

Complement genetic abnormalities

Genetic findings are shown in Table 2. Overall, 34 of 38 patients (89.5%) carried a pathogenic or likely pathogenic complement gene abnormality. Structural variants involving the CFHR1-CFHR3 locus were the leading finding, seen in 30 patients (78.9%); these comprised duplications (n = 19), heterozygous deletions (n = 8), and homozygous deletions (n = 3). CFH abnormalities were identified in 7 patients (18.4%). CFHR5 and CFB abnormalities were each detected in 2 patients (5.3%). No pathogenic variants were detected in CFI, C3, CD46, THBD, or DGKE. Four patients (10.5%) had no identifiable complement gene abnormality despite comprehensive testing; all four had strong AFH antibody positivity.

Table 2 Complement genetic abnormalities in the study cohort.

Gene	Duplication	Heterozygous deletion	Homozygous deletion
CFHR1/3	19	8	3
CFHR5	0	2	0
CFH	0	5	2
CFB	0	2	0

AFH antibody status and combined profiles

AFH antibodies (≥ 100 AU/mL) were detected in 15 patients (39.5%), and 23 patients (60.5%) were seronegative (Table 3). When the genetic and serologic findings were combined (Table 4), three biologic profiles emerged: 11 patients (28.9%) had a combination of complement gene abnormalities and AFH antibody positivity, 23 (60.5%) had isolated complement gene abnormalities, and 4 (10.5%) had isolated AFH antibody positivity without an identifiable complement gene abnormality.

Table 3 Anti-factor H antibody positivity.

Anti-factor H antibody (≥ 100 AU/mL)	n (%)
Positive	15 (39.5)
Negative	23 (60.5)

Table 4 Distribution of complement genetic abnormalities according to anti-factor H antibody status.

Complement genetic abnormality	AFH-positive (n = 15)	AFH-negative (n = 23)	Total n (%)
CFHR1/CFHR3 rearrangements	9	21	30 (78.9)
Duplication	6	13	19
Heterozygous deletion	2	6	8
Homozygous deletion	1	2	3
CFH mutation	3	4	7 (18.4)
Heterozygous mutation	2	3	5
Homozygous mutation	1	1	2
CFHR5 mutation	1	1	2 (5.3)
CFB mutation	1	1	2 (5.3)
No genetic abnormality identified	4	0	4 (10.5)

AFH: Anti-factor H; CFB: Complement factor B; CFH: Complement factor H; CFHR: Complement factor H-related genes.

Pre-transplant disease-directed therapy

Complement dysregulation was recognized before transplantation in 34 patients (89.5%), and only after transplantation in 4 patients (10.5%) during evaluation for graft dysfunction. Pre-transplant immunomodulation consisted of plasma exchange and rituximab in patients with AFH antibody positivity or biologically high-risk genotypes. Among AFH antibody-positive patients receiving therapy, mean antibody levels fell from 179.9 AU/mL at diagnosis to 59.7 AU/mL after treatment, an approximate 67% reduction before transplantation. Two high-risk recipients also received a single 900 mg pre-transplant dose of eculizumab as recurrence prophylaxis.

Recurrence of TMA after transplantation

Recurrent TMA was observed in 7 of 38 recipients (18.4%) (Table 5). All recurrences occurred early, between 1 and 3 weeks after transplantation. Recurrence was biopsy-confirmed in every case. Donor-specific antibodies were negative and C4d staining on graft biopsy was also negative, ruling out antibody-mediated rejection. Tacrolimus trough levels were within the target range, biopsies showed no features of calcineurin inhibitor toxicity, and active infection was excluded at the time of recurrence.

Table 5 Characteristics of recurrence cohort (n = 7).

Case	Complement genetic abnormality	AFH ≥ 100	Genetic details	Pre-transplant treatment	Post-transplant treatment	Outcome
1	Present	Yes	CFHR1-CFHR3 homozygous deletion	-	5 PE + rituximab (500 × 2)	Functioning graft
2	Present	Yes	CFHR1-CFHR3 duplication	6 PE + rituximab 500 mg	Modified immunosuppression	Functioning graft
3	Present	No	CFH heterozygous + CFHR1/3 duplication	3 PE + rituximab 500 mg	4 PE	Functioning graft
4	Present	No	CFHR1-CFHR3 duplication	5 PE + rituximab 500 mg	3 PE + IVIG + bortezomib	Functioning graft
5	Present	No	CFHR1-CFHR3 duplication	-	PE	Graft loss (history of mucormycosis)
6	Present	No	CFHR1 heterozygous	-	4 PE + rituximab 200 mg	Functioning graft
7	Present	No	CFHR1 heterozygous	-	3 PE + eculizumab	Functioning graft

Numbers preceding plasma exchange indicate the number of plasma exchange sessions administered. Rituximab doses are expressed per administration. AFH: Anti-factor H antibody; CFH: Complement factor H; CFHR: Complement factor H-related protein; IVIG: Intravenous immunoglobulin; PE: Plasma exchange.

All recurrences were seen in patients with complement gene abnormalities. No recurrence was observed among the four patients with isolated AFH antibody positivity. The genetic abnormalities in the recurrent group all involved the CFH-CFHR region, and included CFHR1-CFHR3 structural variants (duplications and homozygous deletions) and heterozygous variants in CFH or CFHR1. Two of the seven recurrent patients (28.6%) also had concomitant AFH antibody positivity, both with CFHR1-CFHR3 abnormalities.

Recurrence was managed with plasma exchange and rituximab in most patients, with intravenous immunoglobulin, bortezomib, or eculizumab added in selected cases (Table 5). One patient received a single post-transplant rescue dose of eculizumab and achieved a hematologic response within one week, with sustained renal recovery at last follow-up. Disease control was achieved in all seven recurrent patients.

Renal function after recurrence

Among the recurrent cases, the mean serum creatinine at the time of recurrence was 8.02 mg/dL (median 6.02 mg/dL). Renal function improved rapidly with therapy. By day 7, the mean creatinine had fallen to 2.69 mg/dL (median: 2.62 mg/dL), and remained relatively stable thereafter. The mean values were 3.67 mg/dL at 1 month, 3.51 mg/dL at 3 months, 3.94 mg/dL at 6 months, and 2.17 mg/dL at 1 year. At last follow-up, the mean creatinine was 3.62 mg/dL (median: 2.26 mg/dL).

Causes of death and graft loss

Two deaths (5.3%) occurred during follow-up, both from severe infections. One patient died of nocardial pneumonia complicated by an infected lymphocele, and another died of invasive fungal sepsis. One further patient developed invasive mucormycosis involving the renal allograft, which led to graft nephrectomy and graft loss.

DISCUSSION

Kidney transplantation in complement-mediated kidney disease is challenging because of the risk of post-transplant recurrence and graft failure[3,5,6]. In this single-center cohort of 38 transplant recipients with complement dysregulation, several findings have direct relevance to disease biology, post-transplant recurrence patterns, and treatment strategies in resource-limited settings.

Clinical characteristics

The cohort was relatively young (mean age 36.3 years) with a marked male predominance (84.2%). However, most patients were identified only after progression to advanced kidney failure, with 73.7% on maintenance hemodialysis at the time of complement evaluation. This late presentation is typical of complement-mediated kidney disease in low- and middle-income settings, where atypical or renal-limited phenotypes without overt extra-renal microangiopathic features often remain unrecognized until end-stage kidney disease develops[17]. The high prevalence of hypertension (97.4%) likely reflects this advanced stage; in this context, severe hypertension is both a marker and a consequence of complement-mediated endothelial injury[3,4]. The serologic profile of preserved C4 with reduced C3 in 41.3% of patients indicates predominant alternative pathway activation and supports a complement-mediated rather than immune-complex-driven process[10,11].

Complement genetic abnormalities

A central finding is the high prevalence of complement gene abnormalities (89.5%), with structural variants involving the CFHR1-CFHR3 locus accounting for 78.9% of cases and CFH variants for 18.4%. This differs from Western cohorts, where pathogenic CFH variants typically predominate in 20%-30% of cases[5,10]. This geographic variation likely reflects the genomic architecture of the CFH-CFHR locus on chromosome 1q32, which is susceptible to non-allelic homologous recombination due to extensive sequence homology among CFHR[16]. The resulting deletions, duplications, and hybrid genes alter the balance between FH and CFHR proteins. CFHR proteins can act as competitive antagonists of FH for binding to C3b and surface ligands, and some may stabilize the alternative pathway C3 convertase[18,19]. The net effect is impaired complement regulation at the endothelial surface with sustained alternative pathway activation[12,14]. The predominance of these variants in this cohort is consistent with reports from Indian and South Asian populations[18,21].

AFH antibody positivity

Acquired complement dysregulation was also frequent, with AFH antibodies detected in 39.5% of recipients. This aligns with the known geographic predilection of these autoantibodies in South Asian populations[21]. These antibodies bind the C-terminal domain of FH, impairing surface binding and regulatory function, and producing a phenotype that resembles loss-of-function CFH variants[5,12]. AFH antibodies frequently coexisted with CFHR1-CFHR3 abnormalities; 11 of 15 antibody-positive recipients (28.9% of the cohort) had this combined profile. This supports a two-hit model in which CFHR deletions generate neoepitopes that promote autoantibody formation[6,10]. Recognition of this combined phenotype is clinically important, as it identifies a subgroup in whom both antibody-directed and complement-directed therapies may be required.

Pre-transplant therapy and antibody reduction

Pre-transplant immunomodulation with plasma exchange and rituximab achieved an approximate 67% reduction in AFH antibody titers before transplantation. This is clinically relevant, as elevated titers at transplantation have been associated with early recurrence[6,21]. Plasma exchange removes circulating autoantibodies and may restore functional FH, while rituximab suppresses antibody production through B-cell depletion[5,6]. Rituximab was also used selectively in seronegative patients with prolonged dialysis vintage, recognizing that antibody titers in this setting may underestimate prior antibody-mediated complement dysregulation.

Eculizumab, the standard of care in well-resourced settings[20,23], became available only during the latter part of the study period. Although offered to biologically high-risk recipients, sustained complement inhibition was not feasible in most cases due to cost and limited insurance coverage. A pragmatic approach - a single pre-transplant dose in selected high-risk recipients, with post-transplant use reserved for refractory recurrence - was therefore adopted alongside plasma exchange and rituximab. This strategy was associated with acceptable outcomes despite the absence of routine long-term complement inhibition.

Post-transplant recurrence

The recurrence rate was 18.4% (7 of 38), lower than the 33.3% reported by Merzkani et al[22] and substantially below historical estimates of 75%-90% in CFH mutation-associated disease without complement inhibition[10]. This likely reflects genotype-dependent risk and pre-transplant risk modification. CFH variants and CFH-CFHR hybrid genes confer the highest risk, whereas CFHR1-CFHR3 structural variants - predominant in this cohort - appear to confer an intermediate risk profile[3,5,18]. In addition, pre-transplant antibody profiling and immunomodulation likely reduced antibody-mediated risk[6,21].

All recurrences occurred early, within 1-3 weeks of transplantation, consistent with rapid unmasking of alternative pathway dysregulation following ischemia-reperfusion injury and endothelial activation[3,4,8]. Recurrence was confined to patients with complement gene abnormalities, with no events in those with isolated AFH antibody positivity. This supports the concept that persistent genetic defects, rather than isolated antibody-mediated mechanisms, are the principal drivers of recurrence[8]. Alternative causes were systematically excluded.

Graft outcomes after recurrence

Graft outcomes following recurrence were favorable. Disease-directed therapy successfully controlled the TMA recurrence in all 7 patients (100%), with rapid hematologic and renal recovery. The single graft loss in this group occurred late in follow-up and was due to invasive mucormycosis, unrelated to recurrent TMA. In contrast, Merzkani et al[22] reported graft loss in 78.5% of recurrent cases. The favorable outcomes observed here likely reflect early diagnosis and prompt initiation of therapy. One patient demonstrated sustained response after a single rescue dose of eculizumab[6,21].

Mortality and infectious complications

Overall survival was high, with 94.7% of patients alive at last follow-up. The two deaths (5.3%) were due to severe opportunistic infections - nocardial pneumonia and invasive fungal sepsis. These events occurred in the setting of combined immunosuppression, including induction therapy, plasma exchange, and rituximab, and highlight the cumulative infection risk associated with such regimens[5]. Careful infection surveillance, targeted screening, and appropriate vaccination, including meningococcal vaccination prior to anti-C5 therapy, are essential components of management[6,21].

Limitations and future directions

This study has several limitations. The single-center retrospective design introduces treatment heterogeneity and limits generalizability. The sample size restricts formal subgroup analysis, and only descriptive analyses were performed. Native kidney biopsy was not undertaken in patients on long-term dialysis due to limited diagnostic yield and procedural risk; diagnosis in this group relied on integration of clinical phenotype, genetic testing, AFH antibody profiling, and exclusion of alternative causes. Functional complement assays were not available, and functional validation of variants was not performed. The median follow-up of approximately 12 months may underestimate late recurrence, although early events were consistently captured. Larger prospective multicenter studies incorporating functional assays are required to refine genotype-stratified management and to define the role of sustained complement inhibition[20,23].

CONCLUSION

Kidney transplantation can be successfully performed in selected patients with complement-mediated kidney disease when underlying complement abnormalities are identified and appropriately managed. Early recognition and timely intervention are critical to prevent recurrence and preserve graft function.