Yasuhiro Otsuka

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.

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.

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.

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.

Early recurrence of active IgA nephropathy after kidney transplantation.

IgA nephropathy (IgAN) is recurrent after transplantation; however, its time of recurrence is unpredictable. To date, factors influencing IgAN recurrence have not been elucidated. We present a case of a 23‐year‐old man with end‐stage renal disease (ESRD) who underwent living‐related ABO‐identical pre‐emptive kidney transplantation (PEKT) using his 57‐year‐old mother as a donor. IgAN started when the patient was 19 years old, and renal biopsy revealed the usual pathological findings of IgAN. In spite of steroid therapy including steroid pulse and tonsillectomy, the patient developed nephrotic syndrome and progressed to ESRD in 4 years. Protocol biopsy on day 19 following PEKT revealed active recurrent IgAN. Nephrotic‐range proteinuria and mild deterioration of kidney function developed regardless of strong immunosuppressive therapy such as steroid pulse, double filtration plasmapheresis and rituximab. We report a case of refractory IgAN that recurred 19 days after transplantation. This case is considered of value to elucidate factors leading to active IgAN recurrence.

A case of recurrent light chain deposition disease after living-related renal transplantation – detailed process of the recurrence

A 53‐yr‐old woman with end‐stage renal disease was admitted for renal transplantation (RTX). About a decade ago, she had presented with urinary abnormalities. Monoclonal IgA lambda was detected. Renal biopsy showed nodular glomerulosclerosis, and an immunohistochemical study for lambda was negative. Fibrillary glomerulonephritis was suggested as the most likely diagnosis. RTX was successfully performed, and graft function was stable for the first half year. Graft biopsy was performed at one yr post‐transplant. Glomeruli showed nodular lesion similar to native kidney biopsy findings. Immunofluorescence microscopy (IF) indicated strong lambda staining along the glomerular basement membrane, the tubular basement membrane (TBM), and the peritubular capillary. The diagnosis of recurrent light chain deposition disease (LCDD) was confirmed. A series of biopsies are available to conduct studies on the recurrent process of LCDD. Light microscopy showed no remarkable changes up to six months post‐RTX. However, the IF study revealed evident granular depositions of lambda along the TBM only at the one‐h biopsy. Typical IF staining pattern of lambda and EDD compatible with LCDD were noted after six months post‐transplant. This is the first case report that elucidated the details of the recurrent process of LCDD at one yr after the operation.

Ferrokinetics is associated with the left ventricular mass index in patients with chronic kidney disease

Abstract Background Patients with chronic kidney disease (CKD) often have the complication of anaemia. Usage of an erythropoietin-stimulating agent accelerates iron deficiency because it promotes iron utilization. Recently, iron administration was reported to be effective for patients with cardiac failure. We examined the association between ferrokinetics and cardiac function in patients with CKD. Methods In this cross-sectional study, we examined 558 patients (424 men and 134 women; mean age, 68.9 ± 13.1 years) with CKD who were admitted to our hospital. We assessed cardiac function by ultrasonography and ferrokinetics through transferrin saturation (TSAT) and ferritin levels. Results The primary diseases of CKD were nephrosclerosis (n = 247), diabetic nephropathy (n = 154), chronic glomerulonephritis (n = 73), and others. The mean estimated glomerular filtration rate was 16.9 ± 9.3 mL/min/1.7 m2, and the haemoglobin (Hb) level was 11.0 ± 1.7 g/dL. The median of TSAT was 28.05%, and patients were divided into two groups: below (L-Ts) and above (H-Ts) the median. The median of ferritin was 122 ng/mL, and patients were divided into two groups: below (L-f) and above (H-f) the median. We categorized four groups as H-Ts + H-F, H-Ts + L-F, L-Ts + H-F, and L-Ts + L-F. The Hb levels were 11.1 ± 1.8, 11.3 ± 1.4, 10.9 ± 1.6, and 10.8 ± 1.5 g/dL, respectively, and there was no difference between groups. However, the left ventricular mass indices (LVMIs) were 122.6 ± 46.6, 110.8 ± 32.0, 118.3 ± 36.0, 126.7 ± 46.9, respectively (P = 0.0291). This tendency was stronger in patients without cardiovascular events. Conclusion In patients with CKD, there is an association between ferrokinetics and LVMI. We have to be mindful not only of anaemia but also of ferrokinetics.

Hepatitis B Virus Infection Among Patients With Chronic Kidney Disease Who Attended an Educational Program in Japan: HBV in Patients With CKD in Japan

The rate of hepatitis B infection among hemodialysis patients is high. However, it is not clear if this rate reflects the infection rate among patients with chronic kidney disease (CKD). Therefore, we evaluated the rate of hepatitis B infection among patients with CKD. This is an important clinical issue when considering the risk of infection to medical staff when performing invasive procedures in this clinical population. A retrospective, observational study was conducted among stable, non‐dialysis patients with CKD who attended a CKD educational program at our hospital, between August 2012 and October 2017. We collected patients’ background and markers of hepatitis infection (HBsAg, HBcAb and HBsAb, as well as HBV‐DNA when available) from medical records. The data from 496 patients (373 men and 123 women, with a mean age of 69.3 ± 13.0 years and mean level of creatinine of 3.15 ± 1.72 mg/dL, AST of 21.6 ± 10.5 IU/L, and ALT of 17.3 ± 12.5 IU/L), were included in the analysis. The rate of positive testing for hepatitis B virus infection was as follows: HBsAg, 1.6%; HBsAb, 16.5%; and HBcAb, 21.4%. Of the patients with a negative HBsAg test, 20.1% tested positive for HBcAb. Of the 66 patients in whom HBV‐DNA testing was performed, 10.6% tested positive. The rate of hepatitis B virus infection was specifically higher among patients ≥71‐years‐old. In patients with CKD, the rate of HBsAg positivity is high. Rate of HBcAb positivity is higher particularly in older individuals.

Relationship Between Mortality and Cancer-Bearing Status in Patients With Chronic Kidney Disease Who Attended an Educational Program

Patients with malignancy have a poorer prognosis than others do, which must be taken into consideration when treating them for chronic kidney disease (CKD). However, there are few studies investigating their prognosis. This was an observational study of 515 (394 men and 121 women) stable non‐dialysis patients with CKD who attended a CKD educational program. Mean age was 68.8 ± 13.0 years. Median follow‐up was 968.5 days. Mean creatinine was 3.4 ± 1.6 mg/dL. Of these, 63 had malignancy and 452 did not; 20.6% of the former and 11.9% of the latter group died by the end of the study period (P = 0.0548). Malignancy was not associated with all‐cause mortality (HR: 1.3475, 95% CI: 0.7202–2.5214, P = 0.3507) but with malignancy‐associated mortality (HR: 3.9477, 95% CI: 1.6348–9.5331, P = 0.0023). Renal replacement therapy was not associated with mortality. Since malignancy greatly affects the prognosis, it must be taken into consideration when treating these patients.