Collapsing FSGS in a kidney transplant with a single APOL1 risk variant: a case report

Abstract

Background

Apolipoprotein L1 (APOL1) genetic risk variants substantially increase the risk of chronic kidney disease and kidney failure among individuals of recent African ancestry. While APOL1-associated nephropathy was long considered to follow a recessive inheritance pattern, recent studies have demonstrated an additive effect, indicating that even a single risk variant may be clinically significant. A severe manifestation of APOL1-mediated kidney disease, collapsing focal segmental glomerular sclerosis, has been reported mainly in allografts from donors with two risk variants.

Case presentation

A 60-year-old Surinamese woman of West-African descent with end-stage kidney disease of unknown origin received a kidney transplant from her daughter, with pre-existing donor-specific Class II antibodies detected. The patient experienced delayed graft function, active antibody-mediated rejection, and ultimately developed collapsing focal segmental glomerular sclerosis. Despite intensive treatment, the graft failed, necessitating transplantectomy. Genetic testing revealed a G1G1 APOL1 genotype in the recipient and G1G0 in the donor.

Conclusions

This case suggests that both donor and recipient APOL1 genotypes can contribute to the development of APOL1-mediated kidney disease post-transplantation, and highlights the potential risk associated with even a single APOL1 risk variant in the donor as well as the possible role of the recipient’s APOL1 genotype affecting the immune system. These observations support the consideration of routine APOL1 genotyping in donors of West-African ancestry to improve transplant safety and risk assessment.

Background

Apolipoprotein L1 (APOL1) risk variants are recognized contributors to health disparities in kidney disease among people from West-African descent [1, 2]. Previous studies have demonstrated that donor kidneys with two APOL1 risk variants have a shorter graft survival as compared to kidneys with one or no risk variants [3]. Until recently, the recipient APOL1 genotype was considered non-influential in terms of allograft survival [4]. This fits the paradigm that APOL1 mediated kidney disease (AMKD) is primarily a disease of renal epithelial and endothelial cells. However, progressive insight has demonstrated that the APOL1 genotype of the recipient is also of influence on post-transplant outcomes [5, 6]. One of the more acute and characteristic presentations of AMKD is collapsing type Focal Segmental Glomerular Sclerosis (cFSGS), a histological diagnosis characterized by segmental or global collapse and sclerosis of the glomerular capillary tuft, associated with marked hyperplasia of overlying epithelial cells [7]. cFSGS has been reported in native kidneys with two APOL1 risk variants after a second hit [8]. Additionally, several cases have been published describing the occurrence of cFSGS in kidney allografts from donors with two APOL1 risk variants, independent of the recipient genotype [9–11]. We present a case of a kidney transplant recipient with two APOL1 risk variants who developed cFSGS after receiving a kidney allograft from a donor with only one APOL1 risk variant.

Case presentation

A 60-years old Surinamese female from West African descent received a kidney transplant from her daughter. Prior to transplantation, the patient had been on haemodialysis for nine months due to kidney failure of unknown origin. The medical history of the patient noted rheumatoid arthritis. The HLA mismatch was 0-1-1, and the cross-reactivity Complement-Dependent Cytotoxicity (CDC) test with the donor was negative; however, Luminex testing revealed donor-specific Class II antibodies (DR1, mean fluorescence intensity (MFI) 5000). Both recipient and donor were cytomegalovirus (CMV) immunoglobulin G (IgG) negative and Epstein-Barr virus (EBV) IgG positive. After careful consideration of all options and a shared decision meeting, it was decided to proceed with the transplant procedure.

Immunosuppressive induction therapy consisted of basiliximab (anti-interleukin-2 receptor monoclonal antibodies), followed by maintenance tacrolimus, mycophenolate mofetil and prednisolone. Despite an initially successful transplantation, the patient experienced delayed graft function and hypotension. Ultrasound examination revealed normal findings with good perfusion of the kidney transplant. However, renography demonstrated features consistent with acute tubular necrosis. On day two post-transplantation, a kidney biopsy was performed because of oliguria and suspected rejection. After the biopsy, methylprednisolone 1000 mg daily was started for three days. Three days post-transplantation the patients vital signs improved.

The kidney biopsy (Fig. 1) revealed signs of active antibody mediated rejection (ABMR), C4d was positive for more than 10%. In accordance with protocol, methylprednisolone was complemented with plasmapheresis for seven days, followed by intravenous immunoglobulins (IVIG) 0.5 mg/kg for four consecutive days. Haemodialysis was resumed due to hyperkalaemia. Because of lack of improvement in kidney function, a second biopsy was taken on day fourteen post-transplantation, which showed histological findings consistent with ongoing ABMR (not shown). Anti-thymocyte globulin (ATG) was administered at 2 mg/kg every other day for five doses. Despite these interventions, the patient became anuric. Renography showed decreased kidney transplant perfusion, and, 5 weeks after transplantation, a third kidney biopsy was taken due to suspected ongoing rejection.

Fig. 1.

Kidney transplant biopsy two days post-transplant. A) Well preserved renal parenchyma without chronic damage. Original magnification x10. B) Glomerulus with signs of glomerulitis. Original magnification x40. C) Peritubular capillaries with capillaritis, congestion and interstitial hemorrhage. Original magnification x20. A-C: Jones’ methenamine silver staining

This third kidney biopsy (Fig. 2) showed mild microvascular inflammation, although to a lesser extent than the prior biopsies, consistent with ongoing or subsiding ABMR (C4d negative). Notably, a new histological pattern was observed: cFSGS in nearly all 19 glomeruli examined, which combined with extensive tubular epithelial damage highly suggests AMKD. ABMR treatment was reinitiated. However, renal function did not improve, and the patient developed thrombotic microangiopathy (TMA) with haemolysis a few days later. Ultimately, as the condition of the patient worsened and there was no recovery of kidney function, a transplantectomy was performed. During the post-transplant period the patient was repetitively tested negative for several respiratory viruses, including COVID-19, and gastro-intestinal viruses as well as CMV and EBV.

Fig. 2.

Kidney transplant biopsy five weeks post-transplant. A) Two glomeruli with capillary collapse and epithelial hyperplasia. Mild interstitial inflammation but no signs of rejection. Original magnification x20. B) High magnification of glomerulus with characteristic features of collapsing glomerulopathy; collapse and compression of the capillary tuft, severe hyperplasia of the overlying epithelial cells, which contain vacuoles and protein resorption droplets. Original magnification x40. C) Tubular damage; dilation of tubules and sloughing of tubular epithelial cells. No tubulitis. Original magnification x20. A-C: Jones’ methenamine silver staining

Histologic examination of the transplantectomy specimen (Fig. 3) revealed a fully developed image of AMKD, including complete cFSGS, severe signs of ultrastructural podocyte damage, and extreme tubular dilation and tubular epithelial damage. Notably, no tubuloreticular inclusions were found in the cytoplasm of endothelial cells. The postoperative course was complicated by multiple infectious complications, probably secondary to the prior extensive immunosuppressive therapy.

Fig. 3.

Transplantectomy specimen, six weeks post-transplant. A) Completely collapsed and solidified glomeruli, dilation of Bowman’s capsule. Original magnification x20. B) Tubules show dilation, simplification of tubular epithelial cells and pseudo-thyroidization. Original magnification x10. C) Electron micrograph, showing global effacement and microvillous transformation of podocytes. Original magnification: x9300. A & B: Jones’ methenamine silver staining

Unfortunately, six months after the transplantation, the patient suffered a cardiovascular event during dialysis and, despite resuscitation efforts, deceased. APOL1 genetic testing revealed that the recipient had a G1G1 genotype, while the donor had a G1G0 genotype.

Discussion

Collapsing Focal Segmental Glomerular Sclerosis (cFSGS) is a histological diagnosis based on the presence of at least one glomerulus with collapsed and sclerotic capillaries, along with hypertrophy and hyperplasia of glomerular epithelial cells [7]. Together with tubular epithelial cell damage, cFSGS is one of the characteristic histological presentations of APOL1-mediated kidney disease (AMKD) [12]. Clinically, cFSGS typically presents with an acute onset of rapidly progressive nephrotic syndrome [13]. Several cases of AMKD, presenting as cFSGS, in kidney transplant recipients have been described. Almost all cases involved a donor kidney with two APOL1 risk alleles [9–11, 14], and in four cases, both the donor and recipient had two APOL1 risk alleles [10, 15–18]. There were also two cases reported of cFSGS following a second hit in recipients of donor kidneys with a single APOL1 risk allele [19, 20]. There was one case report similar to our patient, where the recipient had two risk variants and the donor kidney only had one [21]. Taken together, these cases indicate that both donor and recipient APOL1 genotypes can contribute to AMKD development post-transplantation.

Notably, recipient APOL1 genotype has traditionally not been considered a risk factor for graft loss, based on a single retrospective study [4]. However, recent evidence demonstrates that the number of recipient APOL1 risk alleles is associated with death-censored renal allograft loss, potentially through an increased risk of T-cell mediated rejection [5]. Importantly, APOL1 is not only expressed in podocytes and endothelial cells but also in immune cells, including T-cells, B-cells, and NK-cells, where it may modulate immune responses and contribute to graft injury [22]. The impact of APOL1 on transplant outcomes potentially extends beyond podocyte injury alone, and highlights the need for further research into non-podocyte and immune functions of APOL1 in the context of kidney transplantation.

The donor kidney in our case carried only one APOL1 risk variant, which has traditionally been considered clinically irrelevant. However, a study from West-Africa showed that the presence of a single APOL1 risk variant was associated with an increased risk of kidney disease [23]. This finding was further supported by Tassiopoulos et al., who reported an association between a single APOL1 risk variant and chronic kidney disease in patients with human immunodeficiency virus (HIV) from the United States [24]. These observations suggest that even a single APOL1 risk variant from the donor may sufficiently contribute to AMKD in the context of kidney transplantation.

The development of AMKD, including cFSGS, is presumably initiated by a “second-hit”, in which innate immune system activation leads to increased levels of interferon (IFN) and Toll-like receptor stimulation, thereby promoting APOL1 transcription in podocytes and endothelial cells [8, 25–27]. APOL1 transcription can also be upregulated by hypoxia-inducible transcription factors, independent of IFN [28]. In a proposed mechanism, the resulting excess APOL1 forms pores facilitating inappropriate ion conductance, leading to podocyte injury [29–31], compensatory hypertrophy and activation and proliferation of parietal epithelial cells, possibly to compensate for podocyte loss [32]. Numerous second-hits have been described, including other genetic factors, (viral) infections, systemic lupus erythematosus [10, 33, 34], and rejection of a kidney allograft [9]. In our case, the ABMR preceded the histological finding of AMKD, making it the suspected second-hit. ABMR therapy, including IVIG and ATG, could also be a second-hit, as both can increase IFN levels. Infection is the most commonly described second-hit in literature [8, 10]; which cannot be excluded entirely. Several APOL1-independent factors may also have contributed to the development of cFSGS in this case, including thrombotic microangiopathy, other genetic predispositions, and possible recurrence of an underlying (potentially autoimmune) primary kidney disease.

In conclusion, considering the severity of the ABMR, the outcome for this patient would likely have been similar regardless of the presence or absence of APOL1 risk variants. The cFSGS is most likely caused by an interplay between ABMR, acting as a second-hit to the APOL1 risk allele present in the donor kidney, and a possible contribution from the recipient’s homozygous APOL1 genotype affecting the immune system. This highlights the dilemma of kidney donation with APOL1 risk variants and the associated risks for both recipient and donor [35]. Currently, APOL1 genotyping is not routinely performed as part of donor screening in the Netherlands. In line with the KDIGO controversies conference [36], we advise to introduce APOL1 genotyping for living donors of West-African ancestry as a part personalized risk assessment.

Abbreviations

ABMR

Antibody mediated rejection

AMKD

APOL1 mediated kidney disease

APOL1

Apolipoprotein L1 gene

ATG

Anti-thymocyte globulin

CDC

Complement-Dependent Cytotoxicity

cFSGS

Collapsing Focal Segmental Glomerulosclerosis

CMV

Cytomegalovirus

EBV

Epstein-Barr virus

HIV

Human immunodeficiency virus

IFN

Interferon

IgG

Immunoglobulin G

IVIG

Intravenous immunoglobulins

MFI

Mean fluorescence intensity

TMA

Thrombotic microangiopathy

Author contributions

EVS wrote the main manuscript text. JR performed and interpreted the pathological evaluation. MH, FB and JR provided critical revisions to the manuscript. All authors reviewed and approved the final manuscript.

Funding

No funding was received.

Data availability

The data supporting the conclusions of this article are included within the article. Further inquiries can be directed to the corresponding authors.

Declarations

Ethics approval and consent to participate

The present work was conducted in accordance with the Declaration of Helsinki and was approved by the Medical Ethics Committee of the Amsterdam University Medical Center location AMC (number: AMC2016_045). Informed consent was obtained from the donor and family of the patient.

Consent for publication

Informed consent was obtained for publication of this case report from the donor and family of the patient.

Competing interests

The authors declare no competing interests.