The management of antibody-mediated rejection in the first presensitized recipient of a full-face allotransplant.

We report on the management of the first full-face transplantation in a sensitized recipient with a positive preoperative crossmatch and subsequent antibody-mediated rejection (AMR). The recipient is a 45-year-old female who sustained extensive chemical burns, with residual poor function and high levels of circulating anti-HLA antibodies. With a clear immunosuppression plan and salvage options in place, a full-face allotransplant was performed using a crossmatch positive donor. Despite plasmapheresis alongside a standard induction regimen, clinical signs of rejection were noted on postoperative day 5 (POD5). Donor-specific antibody (DSA) titers rose with evidence of C4d deposits on biopsy. By POD19, biopsies showed Banff Grade III rejection. Combination therapy consisting of plasmapheresis, eculizumab, bortezomib and alemtuzumab decreased DSA levels, improved clinical exam, and by 6 months postop she had no histological signs of rejection. This case is the first to demonstrate evidence and management of AMR in face allotransplantation. Our findings lend support to the call for an update to the Banff classification of rejection in vascularized composite tissue allotransplantation (VCA) to include AMR, and for further studies to better classify the histology and mechanism of action of AMR in VCA.

Crescentic fibrillary glomerulonephritis associated with hepatitis C viral infection.

Fibrillary glomerulonephritis (FGN) is a pathological diagnosis that is rarely associated with systemic disorders. In this case report, we describe a woman who presented with FGN of the crescentic type in association with hepatitis C viral infection. The existing literature on the association between these 2 disorders is reviewed, and postulated therapy is presented.

Fibrillary glomerulonephritis: a report of 2 cases with extensive glomerular and tubular deposits.

Deposition of nonamyloid fibrillary material in glomeruli is well known. It is, however, unusual to find these fibrils in the tubular basement membranes and unprecedented to have fibrils of different sizes in the same patient. We present 2 cases with nephrotic range proteinuria with evidence of renal insufficiency. In both cases, strong, polyclonal immunoglobulin (Ig)G with C3 deposits were shown in the glomeruli and along tubular basement membranes. Ultrastructurally, the first case had 28-nm fibrils deposited extensively in the glomeruli and along tubular basement membranes. The second case had 30-nm fibrils in the glomeruli and 15-nm fibrils in the tubules. In both cases, the fibrils did not react with the regular amyloid stains. These findings are used to support the view that fibrillary glomerulopathy is not a disease, but rather the morphologic expression of an etiologically diverse group of diseases as yet incompletely defined.

Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice.

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice developed hypertension (140+/-2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0+/-0.2 mg/g) compared with sham-operated HO-1(+/+) mice (108+/-5 mm Hg and 4.1+/-0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164+/-2 mm Hg) and cardiac hypertrophy (6.9+/-0.6 mg/g) in HO-1(-/-) mice. HO-1(-/-) mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1(+/+) (25%) and HO-1(+/-) (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1(-/-) mice compared with HO-1(+/-) mice. Histological analysis of kidneys from 1K1C HO-1(-/-) mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1(-/-) and 1K1C HO-1(+/-) mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.

A case of fibrillary glomerulonephritis with linear immunoglobulin G staining of the glomerular capillary walls.

We report a case of crescentic glomerulonephritis that presented with extensive crescent formation and fibrinoid necrosis in the glomeruli. Immunofluorescence staining was strongly positive for linear and pseudolinear staining of the capillary walls for immunoglobulin G (IgG) in the absence of significant mesangial staining. Histologic examination and immunofluorescence staining suggested a diagnosis of anti-glomerular basement membrane disease. However, electron microscopy showed the presence of numerous fibrillary deposits in the subepithelial areas of the glomerular capillary walls, supporting the diagnosis of fibrillary glomerulonephritis. Test results for circulating anti-glomerular basement membrane antibodies were negative. We report this interesting case to illustrate the point that fibrillary glomerulonephritis should be considered in the differential diagnosis of crescentic glomerulonephritis with linear and pseudolinear IgG deposits within the capillary walls. In such cases, electron microscopy is critical in differentiating the cause of crescentic glomerulonephritis.

Mechanisms underlying renoprotection during renin-angiotensin system blockade.

Potential determinants of chronic renal disease (CRD) progression were studied in male Munich-Wistar rats subjected to 5/6 nephrectomy and treated with candesartan (Csn; n = 30) or enalapril (Ena; n = 27) from 5 wk postsurgery. Despite control of systolic blood pressure (SBP; 24 wk: Csn = 143 +/- 9; Ena = 148 +/- 8 mmHg), urinary protein excretion rates (U(pr)V) increased over 24 wk (Csn = 92 +/- 10; Ena = 99 +/- 8mg/day). Glomerulosclerosis scores (GS) at 24 wk were similar for Csn (42 +/- 7%) vs. Ena (42 +/- 4%), values close to those of untreated controls at 12 wk (43 +/- 4%). At 24 wk, SBP and UprV correlated strongly with GS, together accounting for 72% of the variance in GS. Renal cortex mRNA levels (determined by competitive RT-PCR) for transforming growth factor (TGF)-beta1 and monocyte chemoattractant protein (MCP)-1 were elevated in Csn and Ena at 12 wk and remained higher at 24 wk vs. sham. Strong correlations were evident among TGF-beta1, MCP-1, and interleukin-1beta and renal injury at 24 wk. Cns and Ena are thus equally effective renoprotective agents in this model. During renin-angiotensin system inhibition, renoprotection is dependent on control of both SBP and UprV. Incomplete suppression of renal cytokine gene expression may also contribute to CRD progression.

Aldosterone: a mediator of myocardial necrosis and renal arteriopathy.

To determine the role of aldosterone in mediating cardiovascular damage, we performed ablation/replacement experiments with aldosterone in a rat model of cardiac injury. Administration of angiotensin II and Nomega-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor) to male rats drinking 1% saline caused hypertension, severe biventricular myocardial necrosis, proteinuria, and fibrinoid necrosis of renal and cardiac vessels. Removal of aldosterone by adrenalectomy or through administration of the selective aldosterone antagonist eplerenone markedly reduced the cardiac and renal damage without significantly altering blood pressure. Aldosterone infusion in adrenalectomized, glucocorticoid-replaced L-NAME/angiotensin II-treated animals restored damage. Thus, we identified aldosterone as a critical mediator of L-NAME/angiotensin II induced vascular damage through mechanisms apparently independent of its effects on systolic blood pressure.

Renal allograft protection with losartan in Fisher-->Lewis rats: hemodynamics, macrophages, and cytokines.

BACKGROUND: We sought to assess the effects of angiotensin receptor blockade on glomerular hypertension, macrophage recruitment, and cytokine expression, all of which contribute to the development of chronic graft injury in this model. METHODS: The effects of treatment with the specific angiotensin II type 1 (AT1) receptor antagonist, losartan, were assessed over 24 weeks in F344-->LEW rats (LOS, N = 9) versus vehicle-treated F344-->LEW controls (CON, N = 9). RESULTS: UprotV rose progressively in CON (from 7.0 +/- 2.9 to 41 +/- 17 mg/day at 24 wk) but remained at baseline in LOS (4.2 +/- 0.6 to 9.4 +/- 1.3 mg/day, P < 0.05 vs. CON). Glomerular capillary pressure (PGC) was increased in CON (71 +/- 1 mm Hg at week 20), but remained within the normal range in LOS rats (54 +/- 2 mm Hg, P < 0.05). Glomerulosclerosis averaged 0.3 +/- 0.2% in LOS versus 4 +/- 2% in CON rats (P < 0.05). Tubulointerstitial injury was minimal in both LOS and CON rats (+). The overexpression of renal cortical cytokine mRNA levels for the monocyte chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and RANTES, as well as interleukin-1, inducible nitric oxide synthase, and transforming growth factor-beta, assessed by competitive reverse transcription-polymerase chain reaction, was suppressed in LOS versus CON rats at 20 weeks. Macrophage and T-cell numbers were decreased, and MCP-1, RANTES, and intercellular adhesion molecule-1 staining in the graft, identified by immunohistochemistry, were attenuated in LOS versus CON rats. CONCLUSIONS: The renoprotective effects of losartan in F344-->LEW rats were associated with lowered PGC, inhibition of macrophage chemoattractants and recruitment, and suppression of macrophage-associated cytokines at 20 weeks. These findings suggest that chronic allograft injury in F344-->LEW rats is, to a large extent, mediated by angiotensin II-dependent mechanisms and that these involve glomerular hemodynamics, macrophages, and macrophage-associated cytokines.

Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and follow-up study.

UNLABELLED: Collapsing glomerulopathy in HIV and non-HIV patients: A clinicopathological and follow-up study. BACKGROUND: Collapsing glomerulopathy (CG) is a pattern of renal injury that is seen in association with HIV infection and that is increasingly recognized in non-HIV patients. METHODS: A review of native kidney biopsies with CG that were diagnosed between 1979 and 1997 in 18 HIV and 42 non-HIV patients is provided. RESULTS: HIV and non-HIV patients with CG were similar in terms of age, sex ratio, serum creatinine, proteinuria, the extent of collapsing and sclerosing glomerular lesions, and interstitial damage. A slight female predominance was found in both groups. In contrast to non-HIV patients, the HIV group was characterized by a high prevalence of blacks (94 vs. 57%), frequent tubuloreticular inclusions (76 vs. 29%), and microcystic tubular changes (72 vs. 40%). In 13 non-HIV patients, CG was associated with a systemic lupus erythematosus (SLE)-like disease (5), hepatitis C virus (HCV) infection (3), HTLV-I infection, MCTD, acute monoblastic leukemia, multiple myeloma, and cerebral arteritis. Overall, the renal survival of human immunodeficiency virus (HIV) and non-HIV patients with CG was not significantly different. Cox regression revealed that HIV infection had an adverse effect on short-term renal survival, with other significant risk factors being extensive interstitial fibrosis, high serum creatinine, proteinuria, and a low percentage of glomeruli with collapse. The slope of reciprocal creatinine was best predicted by the degree of proteinuria. Serum creatinine correlated with the extent of interstitial fibrosis, the male gender, and the percentage of glomeruli with collapse. Proteinuria was best predicted by the extent of effacement of podocyte foot processes. CONCLUSIONS: CG shares many clinicopathological similarities in HIV and non-HIV patients. In some non-HIV patients, CG was associated with autoimmune diseases, lymphoproliferative disorders, and viral infections.

Reversible bilateral hydronephrosis without obstruction in hepatitis B-associated polyarteritis nodosa.

The manifestations of polyarteritis nodosa (PAN) are varied, but urological abnormalities other than ureteric stenosis and orchitis have not been described. We report a case of hepatitis B-associated PAN with bilateral hydronephrosis without obstruction. Retrograde urography conclusively demonstrated the absence of obstruction. Vasculitis-related myopathy, or neuropathy of the ureter, is the most likely cause of this finding. The patient was treated with high-dose steroids, cyclophosphamide, and plasmapheresis with resolution of hydronephrosis. Although the patient required dialysis at initiation of therapy, she went on to recover sufficient renal function to discontinue dialysis. We review the literature on the treatment of hepatitis B-associated PAN and discuss the pitfalls in diagnosis of this condition.

Acute nephrotoxic serum nephritis in complement knockout mice: relative roles of the classical and alternate pathways in neutrophil recruitment and proteinuria.

BACKGROUND: The importance of complement in the pathophysiology of renal disease is still being appreciated. To further address the role of this mediator system, we evaluated the influence of absolute deficiency of C3 and C4 on acute nephrotoxic serum nephritis (NSN). METHODS: Selective 'knockout' of C3 and C4 was routinely confirmed in null mice by ELISA. NSN was induced by intravenous injection of a sheep anti-rat nephrotoxic serum that cross-reacts with murine glomerular antigens. Deposition of heterologous immunoglobulin in wild-type glomeruli was associated with rapid complement deposition and neutrophil infiltration, and followed by the development of proteinuria. RESULTS: Neutrophil infiltration was markedly inhibited in C3-deficient mice indicating a role for complement in PMN recruitment. In contrast, C3 deficiency afforded only partial protection against proteinuria. NSN was studied further in C4 null mice to probe the relative roles of the classical and alternate pathway in disease pathophysiology. C3 and C4 deficiency were associated with equivalent inhibition of PMN recruitment and proteinuria. CONCLUSIONS: In aggregate, the data support a major role for complement in PMN recruitment in this model and point to complement-independent mechanisms of proteinuria in antibody-mediated glomerulonephritis. These 'knockout' mice should prove valuable for defining the complement-activated mediator systems that regulate leukocyte recruitment and tissue injury in renal diseases.