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Commentaries

Toward Deciphering the Code of Pediatric Donor Glomerulopathy

Batal, Ibrahim MD1

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doi: 10.1097/TP.0000000000003039
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Transplantation of pediatric donor kidneys (PDK) into adult recipients is an effective strategy that has helped to expand the organ donor pool.1 In 1991, Truong et al first described a peculiar glomerulopathy, characterized by diffuse glomerular basement membrane (GBM) lamellation and subepithelial electron-lucent material, that developed in a 22-year-old female 33 months after receiving a kidney allograft from an 8-year-old boy.2 Eight years later, Nadasdy et al reported 6 similar cases that developed in kidney allograft recipients from donors aged 6 years or younger. Clinically, these patients had severe proteinuria. Ultrastructurally, allograft biopsies showed diffuse GBM lamellation, reminiscent of that seen in patients with Alport’s syndrome. Prognostically, this glomerulopathy was associated with poor allograft survival, with graft failure developing in 4 of the 7 patients within 3 years posttransplantation.3 Several years later, Choung et al studied renal allograft findings in a cohort of 99 adult patients who received PDK from donors aged 10 years or younger.4 This cutoff was chosen because GBM typically reaches its average thickness (250–300 nm) around 10–12 years of age.5,6 Nine kidney allograft biopsies showed focal or diffuse GBM lamellation accompanied by mesangial sclerosis. The authors used the term “Pediatric Donor Glomerulopathy (PDG)” to designate such lesions.4 Notably, the incidence of GBM lamellation, or PDG, in PDK was 9% in the studies from both Nadasdy et al and Choung et al.3,4 Although these 2 studies support the existence of PDG as a distinct glomerulopathy that develops in a subset of adult patients who receive transplant from PDK, the scope and risk factors for this entity remain unclear. Specifically, the aforementioned studies did not formally test differences between PDG and Alport’s syndrome (eg, by systematically assess the presence of hematuria or immunofluorescence staining for collagen IV) and did not identify predictors of PDG.

In the current issue of Transplantation, Jiang et al7 report one of the largest clinicopathological series of PDG. The investigators assessed allograft biopsies from 121 adults patient receiving PDK (<10-y-old), and defined PDG as segmental or diffuse lamellation of GBM by electron microscopy. PDG was identified in 7 of 121 (6%) of all PDK recipients and in 7 of 23 (30%) of those who had at least 1 allograft biopsy. PDG developed 113–615 days after transplantation, had concurrent microhematuria in 6 (86%) patients, and was only seen in PDK from donors <6-years-old. Five of the 7 biopsies with PDG were associated with additional diagnoses, including BK virus nephropathy (n = 2), T cell-mediated rejection (n = 1), secondary focal segmental glomerulosclerosis (n = 1), and IgA nephropathy (n = 1). Foot process effacement was focal in 6 (86%) of the samples and normal pattern of staining for alpha-3 and alpha-5 subunits of collagen IV was observed in all 7 cases. Notably, average GBM thickness in nonlamellated segments was >250 nm in 3 (43%) PDG cases. However, it should be kept in mind that, in weight-mismatched donor–recipient pairs, a smaller donor allograft adapts to the new environment by rapid posttransplant increase in GBM thickness and glomerular size.8,9

Although predictors of PDG in the total cohort of PDK recipients were not evaluated, in the subset of patients who underwent at least 1 kidney allograft biopsies (n = 23), the authors identified independent associations of PDG with persistent hematuria, younger donor age, and lower donor weight. If replicated by other studies, these features might help identify PDK recipients at increased risk for PDG.

Notably, in this case series with limited follow-up, the investigators have found that PDG was not significantly associated with subsequent deterioration of allograft function, unless associated with other concurrent complications, such as acute rejection, BK virus nephropathy, and IgA nephropathy.

Similar to the studies by Nadasdy et al and Choung et al,3,4 the current study7 only included “for cause” allograft biopsies. Therefore, the actual prevalence of PDG in PDK recipients’ remains unclear and may well exceed the reported incidence of 6%–9%.

The possibility that PDG may be related solely to hereditary nephritis in the donor kidneys appears unlikely, given the unusually high incidence of GBM lamellation in PDK (6%–9%) compared to the estimated incidence of Alport's syndrome in the general population(1:10 000).10 In addition, the lack of characteristic abnormal staining for collagen IV in all 7 cases studied by Jiang et al7 provides additional evidence against Alport’s syndrome in the donor. Potential pathomechanisms of PDG may include physical injury to the immature thin GBM in PDK, which have to adapt rapidly with the different hemodynamic environment in a considerably larger and heavier recipient. Augmented shear stress, rapid growth of the donor kidney, and increased glomerular filtration may all cause cumulative glomerular capillary wall injury that leads over time to GBM splitting and lamellation. Since PDG develop only in a small proportion of adults who receive PDK, one can speculate that additional hits might be necessary for the manifestation of PDG, especially in recipients of kidney from noninfant donors or following dual kidney transplantation (Figure 1). Other potential hits may include injury to endothelium (such as related to severe ischemia-reperfusion injury early in the course of transplantation, alloantibodies, and calcineurin inhibitor toxicity) and/or podocytes (eg, due to mTOR inhibitors and APOL1 high-risk genotypes).

FIGURE 1.
FIGURE 1.:
A 49-y-old Caucasian male with end-stage renal disease attributed to poststreptococcal glomerulonephritis, underwent deceased donor kidney transplantation from an 8-y-old African American male, who died following craniotomy for a Chiari malformation. Donor kidneys were harvested after circulatory death and cold ischemia time was 33 h 27 m. Given the lack of another recipient at the time and the prolonged cold ischemia time in a patient who donated after circulatory death, both donor kidneys were used for an en bloc transplantation. Ten mo after transplantation, the patient presented with urine protein/creatinine of 3.6 g/g, serum creatinine of 1.9 mg/dL, normal serum albumin, and microhematuria (15 RBCs/hpf). The biopsy showed segmental glomerular basement membrane lamellation and the patient developed progressive proteinuria and renal insufficiency leading to graft failure a few months after the biopsy. The development of pediatric donor glomerulopathy despite the en bloc kidney transplantation from an 8-y-old donor would raise the possibility of additional contributing factors. In this case, it is unclear whether the prolonged ischemia time, donation after circulatory death, and potential genetic risk factors in the donor (such as high-risk APOL1) may have contributed to the manifestation and rapid progression of the disease (electron microscopy, original manifestation ×12 000).

Renal transplant pathologists, nephrologists, and transplant surgeons need to be familiar with the diagnosis of PDG. To further our understanding of this unique glomerulopathy, larger multicenter studies and electron microscopic examination of time zero biopsies from PDK would be helpful. While there are presently no effective treatment options, performing routine protocol allograft biopsies—with electron microscopic evaluation—in adult recipients of pediatric kidneys would help delineate the natural history of PDG. Earlier detection of the condition might help delay progression to allograft failure, by intensifying control of other factors that may exacerbate glomerular capillary injury to the thin and immature donor GBM.

REFERENCES

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