Clinical significance of the distribution of C4d deposits in different anatomic compartments of the allograft kidney

Batal, Ibrahim; Girnita, Alin; Zeevi, Adriana; Saab, Bassel Abou; Stockhausen, Sean; Shapiro, Ron; Basu, Amit; Tan, Henkie P.; Morgan, Charles W.; Randhawa, Parmjeet

doi:10.1038/modpathol.2008.152

Cited by 48 publications

(57 citation statements)

References 24 publications

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“…18,19 In our experience, tubular basement membrane staining for C4d in paraffin-embedded tissue is an uncommon phenomenon that is seen in o5% of the allograft biopsies. 22 This staining pattern may not be entirely specific to BK nephropathy because we have seen it occasionally in the absence of active BK virus infection in patients with acute cellular rejection and in one case of recurrent antiglomerular basement membrane glomerulonephritis. 25 However, its presence, especially when accompanied by Bowman's capsule C4d staining, should prompt a more careful examination of the biopsy for viral inclusions.…”

Section: Discussionmentioning

confidence: 95%

“…21 This was also consistent with our observation that, when performed on paraffin-embedded tissue, both diffuse and focal C4d staining patterns were significantly associated with the presence of circulating donor-specific antibodies. 22,23 In individual tubules, staining was considered to be present if more than half of the tubular basement membrane circumference was stained. Staining was further characterized as diffuse, focal, or minimal depending on whether 450%, 10-50%, or o10% of the microscopic fields showed the presence of tubular basement membrane C4d staining, respectively.…”

Section: C4d Stain Interpretationmentioning

confidence: 99%

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The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy

et al. 2009

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Peritubular capillary C4d staining in allograft kidney is an important criterion for antibody-mediated rejection. Whether BK virus infection can result in complement activation is not known. We studied 113 renal allograft biopsies from 52 recipients with a history of BK virus activation. The samples were classified into four groups according to the concurrent detection of BK virus DNA in urine, plasma, and/or biopsy: BK-negative (n ¼ 37), viruria (n ¼ 53), viremia (n ¼ 7), and nephropathy (n ¼ 16) groups. The histological semiquantitative peritubular capillary C4d scores in the viremia (0.3 ± 0.8) and BK nephropathy (0.6 ± 0.9) groups were lower than those in the BK-negative group (1.2±1.1, P ¼ 0.05 and P ¼ 0.06, respectively) and the viruria group (1.2±1.1, P ¼ 0.04 and P ¼ 0.06, respectively). Diffuse or focal peritubular capillary C4d staining was present in 9/76 (12%) and 14/76 (19%) of all samples with concurrent BK virus reactivation (viruria, viremia, and nephropathy). The diagnosis of antibody-mediated rejection could be established in 7/9 (78%) and 5/14 (36%) of these samples, respectively. Diffuse tubular basement membrane C4d staining was restricted to BK nephropathy cases (4/16, 25%). Semiquantitative tubular basement membrane C4d scores were higher in BK nephropathy (1.2 ± 1.3) compared with BK-negative (0.05 ± 0.3, P ¼ 0.017) and viruria (0.0 ± 0.0, P ¼ 0.008) groups. Bowman's capsule C4d staining was more frequent in BK nephropathy (5/16) compared with the aforementioned groups (2/36 (P ¼ 0.023) and 4/51 (P ¼ 0.03), respectively). Within the BK nephropathy group, samples with tubular basement membrane stain had more infected tubular epithelial cells (12.1 ± 7.6% vs 4.4 ± 5.0%, P ¼ 0.03) and a trend toward higher interstitial inflammation scores. In conclusion, peritubular capillary C4d staining remains a valid marker for the diagnosis of antibody-mediated rejection in the presence of concurrent BK virus infection. A subset of biopsies with BK nephropathy shows tubular basement membrane C4d staining, which correlates with marked viral cytopathic effect.

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Section: Discussionmentioning

confidence: 95%

Section: C4d Stain Interpretationmentioning

confidence: 99%

The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy

et al. 2009

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“…Arteriolar C4d staining has been described previously in native kidneys, transplanted kidneys, and other transplanted organs. [19][20][21][22] The etiology of arteriolar C4d deposition is unknown. In light of our data, arteriolar C4d deposition in biopsy samples from patients with TMA may reflect a deficit in complement regulation (such as in aHUS), whereas C4d staining in glomeruli and peritubular capillaries occurs mainly in association with antibody-mediated complement activation (such as in SLE or antiphospholipid syndrome).…”

Section: Discussionmentioning

confidence: 99%

Complement Factor C4d Is a Common Denominator in Thrombotic Microangiopathy

Chua¹,

Baelde²,

Zandbergen³

et al. 2015

Journal of the American Society of Nephrology

102

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Complement activation has a major role in thrombotic microangiopathy (TMA), a disorder that can occur in a variety of clinical conditions. Promising results of recent trials with terminal complement-inhibiting drugs call for biomarkers identifying patients who might benefit from this treatment. The primary aim of this study was to determine the prevalence and localization of complement factor C4d in kidneys of patients with TMA. The secondary aims were to determine which complement pathways lead to C4d deposition and to determine whether complement activation results in deposition of the terminal complement complex. We examined 42 renal sections with histologically confirmed TMA obtained from a heterogeneous patient group. Deposits of C4d, mannose-binding lectin, C1q, IgM, and C5b-9 were scored in the glomeruli, peritubular capillaries, and arterioles. Notably, C4d deposits were present in 88.1% of TMA cases, and the various clinical conditions had distinct staining patterns within the various compartments of the renal vasculature. Classical pathway activation was observed in 90.5% of TMA cases. C5b-9 deposits were present in 78.6% of TMA cases and in 39.6% of controls (n=53), but the staining pattern differed between cases and controls. In conclusion, C4d is a common finding in TMA, regardless of the underlying clinical condition. Moreover, C5b-9 was present in .75% of the TMA samples, suggesting that terminal complement inhibitors may have a beneficial effect in these patients. C4d and C5b-9 should be investigated as possible diagnostic biomarkers in the clinical work-up of patients suspected of having complement-mediated TMA.

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“…BK virus replication in biopsies was assessed using in situ hybridization for viral DNA (Enzo Diagnostics, New York, NY, USA) as previously described (22). Polyclonal C4d (ALPCO Diagnostics, Windham, NH, USA) was performed using published methodology (23). PTC-C4d was graded according to Banff 2007 recommendations (21).…”

Section: Transplant Glomerulitismentioning

confidence: 99%

A Critical Appraisal of Methods to Grade Transplant Glomerulitis in Renal Allograft Biopsies

Batal

Lunz

Aggarwal

et al. 2010

American Journal of Transplantation

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Transplant glomerulitis is an increasingly recognized lesion in renal transplant biopsies. To develop a refined grading system, we defined glomerulitis by the presence of ≥5 leukocytes/glomerulus and evaluated 111 biopsies using three different grading systems: (i) percentage of glomerular involvement, (ii) peak inflammation in the most severely affected glomerulus and (iii) presence/absence of endocapillary occlusion by inflammatory cells. Endocapillary occlusion had no impact on graft survival, but was associated with increased serum creatinine, proteinuria and subsequent transplant glomerulopathy. Grading based on either percent or peak glomerular involvement correlated with graft failure and peritubular capillaritis. However, the percent glomerular involvement method had the additional advantage of displaying associations with: concurrent proteinuria, focal or diffuse immunoperoxidase peritubular capillary C4d staining, 1-year postbiopsy serum creatinine, subsequent detection of donor-specific antibody and development of transplant glomerulopathy. Patients with >75% glomerular involvement also revealed persistent high-grade glomerulitis on follow-up biopsies despite antirejection treatment. In conclusion, grading of glomerulitis is a meaningful exercise, and a quantification system based on percentage of glomerular involvement shows the most robust associations with clinical parameters and prognosis.

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Clinical significance of the distribution of C4d deposits in different anatomic compartments of the allograft kidney

Cited by 48 publications

References 24 publications

The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy

The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy

Complement Factor C4d Is a Common Denominator in Thrombotic Microangiopathy

A Critical Appraisal of Methods to Grade Transplant Glomerulitis in Renal Allograft Biopsies

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