Loss of peritubular capillaries in the development of chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) remains the most important cause of late renal graft loss. In this study, we examined the role of peritubular capillary (PTC) injury in the development of CAN. METHODS: We studied renal biopsies (n = 79) obtained from grafts with CAN. PTC injury was examined morphologically by immunohistochemistry for CD34. These findings were correlated with interstitial fibrosis and graft dysfunction. Humoral immunity involved in CAN was studied by C4d staining. RESULTS: The CAN cases in the present study included chronic rejection (CR) (n = 14, 17.8%) and C4d-positive chronic humoral rejection (CHR; n = 6, 42.9% in CR cases). Irrespective of CR, CHR, or other CAN, the development of CAN was characterized by injury to and loss of identifiable PTCs, accompanied with the development of interstitial fibrosis. In CR and CHR cases, the loss of PTCs was prominent and seemed to progress within a relatively short period after transplantation. A decrease in the number of PTCs significantly correlated with the development of interstitial fibrosis (r = -0.75, P < .001) and impairment of graft function (r = -0.69, P < .001). CONCLUSIONS: Irrespective of whether CR, CHR, or other factors contribute to CAN, the processes involved in its development appear similar and are characterized by progressive injury and loss of PTCs, with the development of renal scarring. Immunohistochemistry for CD34 in human renal biopsies is a useful method for the detection of microvascular injury.     

Prognostic pathologic markers in IgA nephropathy

Previous studies have shown that the overall severity of the histologic grade and the extent of glomerular sclerosis are important pathologic markers of prognosis in IgA nephropathy. A previous analysis of the clinical and pathologic parameters in 74 patients at New York University Medical Center revealed that the renal survival (serum creatinine concentration of 2 mg/dL or less) was 100% in patients with mild proteinuria, 87% in those with moderate proteninuria, and 69% in those with heavy proteinuria. The incidence of segmental and global proliferation, glomerular sclerosis, tubulointerstitial damage, and vessel sclerosis increased with levels of proteinuria (P less than 0.01 to 0.05). A comparison of the morphologic parameters in 30 patients with similar initial serum creatinine concentrations (less than or equal to 2 mg/dL) but different outcomes demonstrates a greater incidence and severity of pathologic features, especially glomerular sclerosis in the "nonsurvival" than "survival" groups. Vessel sclerosis as quantitatively measured by a "point-count" technique correlates with the extent of glomerular sclerosis (r = 0.5192; P less than 0.001), suggesting a causal relationship or common basis.     

IgA nephropathy associated with enteric fever

3 cases of enteric fever (2 paratyphoid and 1 typhoid) associated with IgA nephropathy were reported. Salmonella Vi antigen was demonstrated in the glomeruli. The clinical syndrome disappeared after enteric fever was treated. Possible pathogenesis was discussed relating this intestinal infection to IgA nephropathy.     

Prognostic indicators in childhood IgA nephropathy.

A number of clinical, laboratory and pathologic parameters were assessed for their prognostic significance in 200 children aged less than 15 years with IgA nephropathy, who had shown normal renal function at the time of initial biopsy and were followed for more than 2 years thereafter. After a mean follow-up period of 5.0 years from the initial biopsy, 93 patients had no demonstrable abnormality, 76 had minor urinary abnormalities, 21 had persistent heavy proteinuria and 10 had developed chronic renal impairment. A poor outcome was found to be correlated with heavy proteinuria at biopsy, diffuse mesangial proliferation, a high proportion of glomeruli showing sclerosis, crescents or capsular adhesions, the presence of moderate or severe tubulointerstitial changes, and the presence of subepithelial electron-dense deposits and lysis of the glomerular basement membrane by electron microscopy. The percentage of glomeruli displaying crescents, sclerosis and adhesions appeared to be the most reliable prognostic indicator. Nine of the 27 patients (33%) in whom greater than or equal to 30% of glomeruli showed crescents, sclerosis and adhesions developed chronic renal impairment, and only 14% of these patients had normal urine at follow-up. In contrast, only 1 of the 173 patients in whom less than 30% of glomeruli showed such lesions developed chronic renal impairment (p less than 0.001) and 51% of these patients showed complete remission at follow-up (p less than 0.001). These results demonstrate that an accurate prediction of the outcome based on the initial renal biopsy findings is possible early in the course of children with IgA nephropathy.     

Injury and progressive loss of peritubular capillaries in the development of chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) remains the most important cause of late renal graft loss. However, the mechanism for graft dysfunction and the process of the development of CAN are not well understood. This study examined the role of microvascular injury in the development of CAN. METHODS: We studied renal biopsies obtained from grafts with CAN (N= 79) and pretransplant control kidneys (N= 20). Microvascular injury was examined morphologically, and was correlated with interstitial fibrosis, glomerular sclerosis, graft function, and the severity of CAN. The humoral and cellular immunity involved in CAN were examined by C4d, CD3, and TIA-1 staining. RESULTS: In all the cases of CAN, microvascular injury was evident with or without CD3-positive T cells, TIA-1-positive cytotoxic cells, and/or C4d+ complement deposition. Irrespective of chronic rejection (N= 14), C4d+ chronic humoral rejection (N= 6), or other CAN, the development process of CAN was characterized by injury and progressive loss of identifiable peritubular capillaries (PTCs) accompanied with the development of interstitial fibrosis. Injured PTCs were characterized morphologically by the process of angioregression with the presence of apoptotic cells, lamination of the basement membrane, and loss of PTCs. The low number of PTCs correlated significantly with the severity of CAN (r=-0.74, P < 0.001), the development of interstitial fibrosis (r=-0.75, P < 0.001), graft dysfunction (r=-0.69, P < 0.001), and also correlated weakly with proteinuria (r=-0.45, P < 0.05). In the glomeruli, capillary loss significantly correlated with the degree of glomerular sclerosis (r=-0.66, P < 0.001) and proteinuria (r=-0.65, P < 0.001), but did not correlate with the severity of CAN (r=-0.24, P > 0.05) or graft dysfunction (r=-0.32, P > 0.05). CONCLUSION: CAN was characterized by progressive injury to the renal microvasculature and the development of renal scarring. In particular, injury, angioregression and progressive loss of the PTC network strongly contributed to the development of interstitial fibrosis and graft dysfunction in CAN, and might play a crucial role in the development of CAN.     

Persistent rejection of peritubular capillaries and tubules is associated with progressive interstitial fibrosis

BACKGROUND: We have reported that a 12-day course of high dose cyclosporine A treatment in thymectomized miniature swine with major histocompatibility complex (MHC) class I-mismatched renal allografts results in transient acute rejection followed by either in chronic rejection (progression group) or graft acceptance (recovery group). Here, we examined the differential features between both groups in the peritubular capillaries (PTCs) and tubules to clarify the pathogenesis of the progressive interstitial fibrosis in chronic rejection. METHODS: Morphometric and immunohistochemical studies were performed on serial renal biopsies (days 0 to 100) obtained from both groups, focusing on the cellular infiltrate, rejection of PTCs and tubules, myofibroblast accumulation, and progressive interstitial fibrosis. RESULTS: In the progression group, acute rejection occurred by day 8 and progressed to chronic rejection by day 100, with the development of interstitial fibrosis. PTC endothelial cell and tubular epithelial cell death associated with CD3+ cell infiltration was evident, confirmed by nick end-labeling (TUNEL), commencing by day 8 and continuing thereafter. In acute rejection, destruction of PTCs and tubules accompanied by disruption of basement membrane (BM) occurred with capillaritis or tubulitis in areas with a severe cellular infiltrate. During the development of chronic rejection, capillaritis of PTCs and tubulitis continued by day 100, accompanied by persistent T cell infiltration, and the remaining PTCs and tubules exhibited progressive atrophy with thickening and/or lamination of BM. On day 100, identifiable PTCs and tubules were lost in areas of interstitial fibrosis. Proliferating (PCNA+) alpha-actin+ myofibroblasts accumulated around PTCs, tubules and in interstitium, and widespread interstitial fibrosis developed by day 100. In contrast, in the recovery group, injured PTCs and tubules recovered by day 100 based on the resolution of acute rejection, and minimal loss of PTCs and tubules was evident by day 100 with minimal interstitial fibrosis. CONCLUSIONS: Persistent rejection directed at PTCs and tubules, and proliferation of myofibroblasts are prominent features in the progressive interstitial fibrosis in chronic rejection, and are probably key events in its pathogenesis.     

Nephrotic IgA nephropathy associated with disseminated tuberculosis

A 35-year-old woman who had been suffering from ascites more than 3 months after the delivery of her first baby, developed generalized edema, pyrexia, pleural effusion, and right lower abdominal pain. The laboratory data revealed 5.6 g of 24-hour urinary protein, increased ESR and CRP, a positive skin test for tuberculosis, and a positive culture fortuberculous bacilli from pleural effusion. A renal biopsy showed mild proliferative glomerulonephritis, IgA and C3 depositions along the capillary loop, in the mesangium and also in the focal tubular basement membrane, and scattered membranolysis of the glomerular basement membrane in addition to paramesangial and intramembranous electron-dense deposits. A positive culture of tuberculous bacilli led anti-tuberculous drugs resulted in the complete disappearance of proteinuria, inflammation, and various organ manifestations. As far as we know, the association of tuberculosis with glomerulonephritis is an uncommon occurrence. In addition to describing this case, we also discussed the role of tuberculosis in the pathogenesis of glomerulonephritis, and reviewed the pertinent literature.     

C4d deposition in the glomeruli and peritubular capillaries associated with transplant glomerulopathy

Transplant glomerulopathy (TGP) is a unique disease entity with characteristic pathological findings. Although ultrastructural studies for TGP have been performed, histogenesis of TGP is not fully understood. The present study was designed to investigate the relation of complement fragment C4d to the histogenesis of TGP. Nine cases of isolated TGP were randomly selected. A commercially available monoclonal antibody against complement fragment C4d was used in allograft biopsies. To evaluate the extent and severity of deposition of the C4d complement in the glomerular and peritubular capillaries, indirect immunofluoresce method was performed on frozen sections. Intense deposition of C4d in the glomerular basement membrane and peritubular capillaries was found in association with morphological appearance of TGP. Peritubular capillaries were affected in all the patients, showing splitting and multilayering of peritubular capillary basement membrane. These changes, which diffusely affect most capillaries, and their severity pattern were quite similar in each patient. In early stages of all patients with cellular rejection, C4d was not detected in the glomerular and peritubular capillaries. In addition, no C4d deposition was detected in all zero-hour biopsies without diagnostic abnormality. These findings suggest that C4d deposition in the glomerular and peritubular capillaries might be associated with the pathogenesis of TGP in renal transplantation.     

伴有高血压的IgA肾病临床病理与预后分析

目的探讨伴有高血压的IgA肾病的临床表现和病理特点的关系。方法回顾性分析我科经肾脏活体组织检查诊断为IgA肾病82例患者的一般情况、临床表现、病理资料。根据病程中血压状况分为高血压组（A组）33例;非高血压组（B组）49例。比较2组的临床和病理资料。结果A组伴有高血压的IgA肾病患者,占同期IgA肾病的40．24％。A组贫血、高尿酸血症、肾功能不全发生率高于B组（P〈0．05）,24h尿蛋白定量大于B组（P〈0．05）,而水肿、血尿的发生率无统计学差异。A组IgA肾病病理损害重度者的比例高于B组,病理类型以MsPGN为主,占60．61％。肾小球硬化和血管病变发生率较高、肾间质病变程度较重（P〈0．05）,新月体形成率较低（P〈0．05）。结论伴有高血压的IgA肾病患者高尿酸血症、肾功能不全发生率高,24h尿蛋白量大,病理损害较重,预后较差。     

伴有高脂血症的IgA肾病临床和病理分析

目的 探讨伴有高脂血症的IgA肾病临床表现和病理特点的关系.方法 回顾性分析我科经肾活检诊断为IgA肾病86例患者的一般情况、临床表现、病理资料.根据病程中患者血清脂质水平,分为高脂血症组40例和非高脂血症组46例.比较2组临床和病理资料.结果 高脂血症组血尿酸和24 h尿蛋白定量高于非高脂血症组,估算肾小球滤过率(e...     

白蛋白活化肾小管上皮细胞对肾小管周微血管的影响及机制研究

目的 探讨人类血清白蛋白（HSA）超负荷损伤肾小管上皮细胞后对肾间质微血管损伤的影响及可能机制。 方法 激光共聚焦显微镜观察肾小管上皮细胞（HKC）吞饮罗丹明标记白蛋白（TRITC-BSA）以及吞饮受体cubilin siRNA对其的抑制效应。氢化乙锭标记的荧光探针检测白蛋白刺激HKC产生O2－以及白蛋白吞饮受体cubilin siRNA和线粒体呼吸链复合物I抑制剂鱼藤酮对HKC产生O2－的抑制作用。培养上清H2O2采用化学比色方法检测。倒置显微镜下观察HSA激活的HKC以及cubilin siRNA或鱼藤酮预处理的HKC与脐静脉内皮细胞（HUVEC）共培养后血管内皮管样结构形成情况。四甲基偶氮唑盐（MTT）比色法测定内皮细胞活力。用流式细胞仪以AnnexinV FITC/PI双染法检测内皮细胞凋亡率。 结果 （1）cubilin siRNA可显著抑制HKC吞饮白蛋白(P ＜ 0.05)。（2）HSA刺激HKC产生 ROS呈剂量及时间依赖性(P ＜ 0.05)；cubilin siRNA及鱼藤酮均可抑制白蛋白超负荷诱导HKC产生大量ROS (P ＜ 0.05)。（3）HKC与HUVEC共培养体系中，HSA活化的HKC抑制内皮细胞管样结构的形成，内皮细胞增殖显著减少(P ＜ 0.05)，细胞凋亡率显著增高(P ＜ 0.05)；而cubilin siRNA和鱼藤酮干预组内皮细胞管样结构数及内皮细胞活力显著增加(P ＜ 0.05)，细胞凋亡率显著降低(P ＜ 0.05)。 结论 白蛋白可通过吞饮受体cubilin激活肾小管上皮细胞线粒体呼吸链复合物I产生大量ROS，后者可能是慢性肾病时大量蛋白尿活化肾小管上皮细胞进而损伤肾小管周微血管网的重要介质。     

Acute interstitial nephritis associated with IgA nephropathy in children

IgA nephropathy (IgAN) is a relatively common glomerulopathy in children and adolescents. The etiology of this disease is uncertain. We previously reported a child with IgAN who developed acute interstitial nephritis. We now describe three pediatric patients, including the index case, who had IgAN and who developed concomitant acute interstitial nephritis in association with renal functional impairment. We suggest that this histopathological lesion be considered in any child with IgAN and unexpectedly severe kidney dysfunction. Received January 19, 1996; received in revised form and accepted June 10, 1996     

Homozygous C3 deficiency associated with IgA nephropathy

A 23-year-old male patient with homozygous C3 deficiency who developed asymptomatic proteinuria and hematuria was reported. Renal biopsy disclosed typical IgA nephropathy with deposition of early- and late-complement components except for C3 deposition. C9 and membrane attack complex were detected in the glomeruli despite the absence of C3. It was suggested that there might be some unknown complement activation mechanism which does not require C3 component.