Keiji Horike

Complement fragment C4d deposition in peritubular capillaries in acute humoral rejection after ABO blood group-incompatible human kidney transplantation.

Background. Acute humoral rejection (AHR) is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) kidney transplantation (RTx). The pathogenesis and diagnostic criteria for AHR after ABO-i RTx remain unclear. Complement fragment C4d deposition in peritubular capillaries (PTC), which is a sensitive indicator for activation of the classical complement pathway, was studied to establish the pathologic diagnostic indicator of AHR. Methods. Forty-four graft biopsy specimens from 19 patients with ABO-i living donors were analyzed within 90 days after RTx. Nineteen biopsy specimens with acute rejection after ABO-compatible (ABO-c) living-related RTx were used as controls. Diffuse and bright C4d deposition in PTC was considered significantly positive. Results. All of 8 recipients with AHR showed significantly positive C4d in PTC in the ABO-i group, but 9 of 11 recipients without AHR were negative. In the ABO-c RTx group, 16 of 19 recipients were negative for C4d in PTC. The prevalence of C4d in PTC was significantly higher in ABO-i RTx (P <0.05). Conclusions. C4d deposition is valuable as a specific and sensitive indicator for AHR, even of mild severity, in ABO-i RTx.

Decreased glomerular filtration as the primary factor of elevated circulating suPAR levels in focal segmental glomerulosclerosis

BackgroundCirculating factor(s) has been thought to be the underlying cause of focal segmental glomerulosclerosis (FSGS), and recent studies foster this idea by demonstrating increased soluble urokinase receptor (suPAR) levels in the serum of FSGS patients.MethodsTo explore the possible contribution of suPAR in FSGS pathogenesis, we analyzed serum suPAR levels in 17 patients with FSGS and compared them with those in patients with steroid-sensitive nephrotic syndrome, chronic glomerulonephritis, or non-glomerular kidney diseases.ResultsSerum suPAR levels in patients with FSGS were higher than those in patients with steroid-sensitive nephrotic syndrome or chronic glomerulonephritis, but not higher than those in patients with non-glomerular kidney diseases. suPAR levels negatively correlate with estimated glomerular filtration rate and were decreased after renal transplantation in patients with FSGS as well as in those with non-glomerular kidney diseases. Furthermore, 6 FSGS patients with post-transplant recurrence demonstrated that suPAR levels were not high during the recurrence.ConclusionsBased on our results, elevated suPAR levels in FSGS patients were attributed mainly to decreased glomerular filtration. These data warrant further analysis for involvement of possible circulating factor(s) in FSGS pathogenesis.

Benefits of cyclosporine absorption profiling in nephrotic syndrome: preprandial once-daily administration of cyclosporine microemulsion improves slow absorption and can standardize the absorption profile.

Aim:  Cyclosporine is known to improve proteinuria in nephrotic syndrome (NS), but is also associated with drug‐related renal impairment. In this case series, therapeutic drug monitoring using the absorption profile was applied to adults with NS to investigate the efficacy and safety of once‐daily administration of cyclosporine microemulsion (CSAME).

Recurrent glomerular disease after kidney transplantation: An update of selected areas and the impact of protocol biopsy

Recurrence of native kidney disease following kidney transplantation affects between 10% and 20% of patients, and accounts for up to 8% of graft failures. In a considerable number of recipients with transplant glomerulopathy, it is impossible to distinguish between recurrent and de novo types. An accurate estimate of the incidence of recurrence is difficult due to limitations in the diagnosis of recurrent glomerulonephritis. De novo glomerular lesions may be misclassified if histological confirmation of the patients native kidney disease is lacking. Asymptomatic histological recurrence in renal allografts may be missed if protocol biopsies are not available. Studies based on protocol biopsy are pivotal to accurately estimate the incidence of recurrence. Many factors are known to influence recurrence of kidney disease after transplantation, including the type and severity of the original disease, age at onset, interval from onset to end‐stage renal disease, and clinical course of the previous transplantation. Early recognition of recurrence is possible in several glomerular diseases. Factors such as the existence of circulating permeability factors, circulating urokinase receptor and anti‐phospholipase A2 receptor antibody, as well as disorders of complement regulatory proteins like factor I mutation and factor H mutation factors are expected to be useful predictors of recurrence. Peculiar clinical course of atypical haemolytic uremic syndrome after kidney transplantation is an informative sign of recurrent glomerular disease. These factors play pivotal roles in the development of recurrence of certain types of glomerulopathies. Understanding the pathogenesis of recurrent glomerulonephritis is critical to optimize prevention as well as treat individual cases of recurrent glomerulonephritis. Subclinical recurrence of IgA nephropathy after kidney transplantation is well recognized. Only protocol biopsies of clinically silent recipient can provide the accurate prevalence of recurrent IgA nephropathy. The study of recurrent glomerulonephritis will contribute not only to improving long‐term graft survival, but also to clarifying the pathogenesis of glomerulonephritis. Protocol biopsy is one the most effective methods for elucidating the pathogenesis of recurrent glomerulonephritis.

A recurrent fibronectin glomerulopathy in a renal transplant patient: a case report.

Fibronectin glomerulopathy (FNG) is a rare, autosomal dominant renal disease with massive mesangial, and subendothelial fibronectin deposits. It presents proteinuria, often in the nephrotic range in the third to fourth decade, and slow progression to end‐stage renal disease. The risk of recurrent disease in renal allograft is uncertain. A Japanese female with end‐stage renal disease because of unknown origin received a renal transplant and was referred with proteinuria and mild deterioration of renal function four months after transplantation. Five allograft biopsies were underwent from one h to 12 months after the transplantation, including a biopsy 19 d after the transplantation, which revealed dense deposits suggesting fibronectin. A biopsy 134 d after the transplantation showed a feature of lobular glomerulonephritis corresponding FNG. The diagnosis was confirmed by IST4 positive and IST9 negative immunostaining together with typical fibrillary dense deposits in the mesangium and subendothelial spaces in electron microscopy. This is the first report of recurrent FNG in Japan.

Insidious transmission of membranous nephropathy from kidney donor with no clinical manifestations before and after transplantation

Abstract:  Live kidney donors are supposed to have no clinical kidney disease. Here, we present a unique case of subclinical membranous nephropathy (MN) from a living donor, who had urinalysis‐free stable kidney function pre‐ and post‐transplant. A 39‐yr‐old Asian woman received a second kidney graft from her spouse whose urinalysis and blood chemistry were stable and normal. Her intraoperative one‐h core biopsy revealed thick glomerular basement membrane (GBM) and a bubbly type appearance, compatible with stage II MN on Churg’s classification. According to two other protocol biopsies, GBM thickening persisted until month six post‐transplant. Interestingly, both the donor and the recipient had stable kidney function without overt proteinuria at each monthly visit until one yr post‐transplant. Taken together, we speculate that “silent” MN may exist in certain healthy individuals, who present only with histopathologically compatible MN and no other findings.

Significance of C4d deposition in antibody‐mediated rejection

The C4d staining as a special tissue marker for humoral immunity has served criteria of pathological diagnosis for antibody‐mediated rejection (ABMR) in Banff classification since 2003. However, the sensitivity and specificity of C4d staining have been questioned, and recently, C4d‐negative ABMR has been more focused in renal allograft pathology. The aim of this study was to make certain of C4d staining for ABMR that was diagnosed by clinical and morphological findings. C4d staining was employed by immunofluorescence. This study included 14 patients with acute ABMR and 16 with chronic active ABMR. Eight of acute ABMR were ABO‐blood‐type‐incompatible renal transplantation (ABOinRTx) pre‐treated by DFPP and splenectomy or rituximub. In acute ABMR after ABOinRTx, C4d staining along peritubular capillary (PTC) was positive in five of them (62.5%). Only one graft biopsy of five acute ABMR with donor‐specific antibody (DSA) showed C4d positive. We assembled 16 graft biopsies showing typical transplant glomerulopathy and thickened PTC basement membrane with peritubular capillaritis as a suspicious pathological chronic active ABMR. Four of eight DSA‐positive patients were C4d negative in PTC; however, three of four DSA‐positive and C4d‐negative patients in PTC chronic active ABMR were C4d positive in only glomerular capillaries. C4d positivity could not come to a specific marker of ABMR diagnosing based on clinically and ordinary morphological findings.

Current problems of chronic active antibody-mediated rejection.

Takeda A, Horike K, Ohtsuka Y, Inaguma D, Goto N, Watarai Y, Uchida K, Morozumi K. Current problems of chronic active antibody‐mediated rejection.
Clin Transplant 2011: 25 (Suppl. 23): 2–5.
© 2011 John Wiley & Sons A/S.

Oral carbonaceous absorbent modifies renal function of renal ablation model without affecting plasma renin-angiotensin system or protein intake.

AbstractBackground. Although it has been repeatedly shown that the oral carbonaceous absorbent AST-120 ameliorates the progression of chronic renal failure, the mechanisms remain unknown. Methods. Male Sprague-Dawley rats (6 weeks old), weighing 180–210 g, were 4/5 nephrectomized, and were divided into two groups: one given AST-120 (0.4 g/100 g body weight BW; n = 9) and the other not given AST-120 (n = 9). Body weight, blood pressure, and serum and urine chemistry, as well as the plasma components of the renin-angiotensin system, were measured for 22 weeks. Results. Proteinuria was significantly greater in the controls than in the AST-120 group (102 ± 22 vs 51 ± 7 mg/day at 22 weeks). Urea clearance was lower in the former (3.7 ± 0.4 vs 3.9 ± 0.4 ml/min). There were no differences in plasma renin activity (1.4 ± 0.3 vs 1.9 ± 0.4 mg/ml per h), or in angiotensin I (756 ± 119 vs 1042 ± 168 pg/ml) and II (35.1 ± 7.4 vs 46.6 ± 7.6 pg/ml) or angiotensin-converting enzyme activity (39.0 ± 2.4 vs 37.9 ± 2.2 IU/l) between the two groups. Protein intake, estimated from urinary urea appearance, was not different. Serum phosphate concentration (6.6 ± 0.3 vs 5.9 ± 0.3 mg/dl) was higher in the control than in AST-120, while the urinary phosphate excretion rate (31.5 ± 0.8 vs 28.1 ± 1.8 mg/day) tended to be lower in the latter. Conclusions. AST-120 retarded the progression of renal failure in the 4/5 renal ablation model without affecting the plasma renin-angiotensin system or protein intake, both of which were the most important risk factors for the progression of renal failure. We hypothesize that the renal protective effects of the oral absorbent AST-120 may be, at least in part, due to its lowering phosphate absorption from the diet as a phosphorus binder.

Is arteriolar vacuolization a predictor of calcineurin inhibitor nephrotoxicity

Horike K, Takeda A, Yamaguchi Y, Ogiyama Y, Yamauchi Y, Murata M, Kawaguchi T, Suzuki T, Otsuka Y, Inaguma D, Goto N, Watarai Y, Uchida K, Morozumi K. Is arteriolar vacuolization a predictor of calcineurin inhibitor nephrotoxicity?
Clin Transplant 2011: 25 (Suppl. 23): 23–27.
© 2011 John Wiley & Sons A/S.