The Donor Kidney Biopsy and Its Implications in Predicting Graft Outcomes: A Systematic Review.

Despite a growing organ shortage in the United States, many deceased donor kidneys removed for transplantation are discarded. Kidney biopsy findings often play a role in these discards, although it is not clear whether biopsies reliably inform acceptance decisions. Therefore, we carried out a systematic review of the medical literature on the utility of both procurement and implantation biopsies for predicting posttransplant outcomes. Between January 1, 1994 and July 1, 2014, 47 studies were published in the English language literature that examined the association between pretransplant donor biopsy findings from 50 or more donors (with more than half being from deceased donors) and either posttransplant graft failure, delayed graft function, or graft function. In general, study quality was poor. All were retrospective or did not indicate if they were prospective. Results were heterogeneous, with authors as often as not concluding that biopsy results did not predict posttransplant outcomes. The percent glomerular sclerosis was most often examined, and failed to predict graft failure in 7 of 14 studies. Of 15 semiquantitative scoring systems proposed, none consistently predicted posttransplant outcomes across studies. Routine use of biopsies to help determine whether or not to transplant a kidney should be reexamined.

Expression of cyclin-dependent kinase inhibitor p21 in human liver.

The p21 protein is a universal inhibitor of cyclin-dependent kinases and of cell-cycle progression and is involved in numerous growth-inhibitory pathways in cell culture systems. Recent studies suggest that p21 regulates hepatocyte cell cycle progression in models of liver regeneration. The present study was designed to investigate the possible involvement of p21 in the control of hepatocyte proliferation in human liver diseases. To examine that, the expression of p21 in clinical liver biopsy specimens was determined by immunohistochemistry. This was correlated with hepatocyte Ki-67 immunostaining (a marker of hepatocyte proliferation in vivo) as well as histologic features. Little p21 or Ki-67 expression was detected in normal human liver or in specimens of nonalcoholic steatohepatitis. In patients with alcoholic hepatitis, increased expression of p21, but not of Ki-67, was observed. In specimens with chronic hepatitis C, hepatocyte p21 expression was significantly correlated with Ki-67 immunostaining, as well as with the degree of inflammation and fibrosis. These results indicate that hepatocyte p21 expression is upregulated in response to hepatic injury and correlates with histologic markers of proliferation and disease activity. This study provides evidence that p21 plays a role in the regulation of hepatocyte proliferation in human liver diseases.

Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver.

In tissue culture systems, p21 and p27 inhibit cyclin-dependent kinase (CDK) activity and cell cycle progression in response to numerous stimuli, but little is known about their involvement in cell growth in vivo. We examined the modulation of CDK activity by these proteins after 70% partial hepatectomy (PH), an in vivo model of synchronous hepatocyte cell cycle progression. After PH in BALB/c mice, p21 was induced during the prereplicative (G1) phase and was maximally expressed after peak hepatocyte DNA synthesis. p27 was present in quiescent liver and was minimally induced after PH. p21 and p27 immunoprecipitated with CDK2, CDK4, and cyclin D1 in the regenerating liver. The activity of CDK2-, CDK4- and cyclin D1-associated kinases was upregulated after PH, and maximal activity of these enzyme complexes corresponded to peak DNA synthesis. Immunodepletion experiments suggested that p27 plays a role in downregulating CDK2 activity before and after peak DNA synthesis. Compared to cogenic wild-type mice, p21-/- mice demonstrated evidence of markedly accelerated hepatocyte progression through G1 phase after PH: DNA synthesis, upregulation of cyclin A and PCNA, induction of cyclin D1- and CDK2-associated kinase activity, and appearance of a phosphorylated retinoblastoma protein (Rb) species occurred earlier in the p21-/- mice. These results suggest that p21 and p27 modulate CDK activity in the regenerating liver, and that p21 regulates the rate of progression through G1 phase of the cell cycle in vivo.

Irbesartan lowers blood pressure and ameliorates renal injury in experimental non-insulin-dependent diabetes mellitus.

In the present study, we investigated the effects of the angiotensin (Ang) II receptor antagonist, irbesartan, on blood pressure and renal structural injury in obese Zucker rats (OZR), an experimental model of non-insulin-dependent diabetes mellitus (NIDDM). Twenty-six-week-old OZR with established renal disease were administered either low-dose (15 mg/kg) or high-dose (50 mg/kg) irbesartan in the drinking water for a period of 18 weeks. Irbesartan caused dose-related reductions in blood pressure, and reduced by 47 to 60% the percent of glomeruli with sclerosis at 44 weeks of age (P < 0.05). In addition, irbesartan at the higher dose reduced the tubulointerstitial injury score at 44 weeks by approximately 75% (P < 0.05). By contrast, irbesartan did not significantly reduce albuminuria in OZR. The results of the present study demonstrate that the Ang II receptor antagonist irbesartan can reduce blood pressure and ameliorate glomerular and tubulointerstitial injury in an experimental model of NIDDM.

The angiotensin II receptor antagonist losartan reduces blood pressure but not renal injury in obese Zucker rats.

Agents that interfere with the renin-angiotensin system (RAS) may ameliorate progressive renal injury, particularly in a setting where intrarenal RAS activity appears to be elevated. Whether RAS antagonists affect renal disease progression when intrarenal RAS activity is not increased is unclear. In this study, therefore, the effects of the angiotensin II receptor antagonist losartan on glomerular and tubulointerstitial injury were investigated in obese Zucker rats (OZR), an experimental model of progressive renal disease characterized by reduced intrarenal renin content and reduced plasma renin activity. Losartan (100 or 200 mg/L of drinking water) was administered to OZR beginning at 26 wk of age, when renal disease was established. At 38 and 44 wk of age, losartan-treated OZR demonstrated significant (P < 0.05) dose-related decreases in systolic blood pressure, compared with blood pressures in untreated, control OZR. Despite the reductions in blood pressure, losartan had no significant effects on albuminuria or glomerular or tubulointerstitial injury. At 44 wk of age, the percentage (mean +/- SE) of glomeruli with sclerosis was 51 +/- 11, 49 +/- 9, and 39 +/- 14% in control OZR, low-dose (100 mg/L) losartan-treated OZR, and high-dose (200 mg/L) losartan-treated OZR, respectively (P > 0.05). Similarly, the tubulointerstitial injury score (range, 0 to 4) in the three groups was, respectively, 1.7 +/- 0.4, 1.6 +/- 0.3, and 1.5 +/- 0.3 (P > 0.05). It was concluded that in a setting of chronic renal failure where intrarenal RAS activity does not appear to be increased, angiotensin II receptor antagonism may not be nephroprotective despite a reduction in blood pressure.

De novo immunotactoid glomerulopathy of the renal allograft: possible association with cytomegalovirus infection.

A 59-year-old man with end-stage renal failure from systemic vasculitis developed de novo immunotactoid glomerulopathy of the renal allograft, with clinical evidence of hematuria, proteinuria, and acute renal failure 6 weeks after cadaveric renal transplantation. The morphologic lesion of immunotactoid glomerulopathy and the clinical renal disease resolved during the following 2 weeks. The disease had not recurred in the subsequent 20 months of posttransplant follow-up. During the same period, the patient also developed systemic cytomegalovirus (CMV) infection with viremia, acute hepatitis, and bone marrow suppression. The clinical manifestations of CMV illness and the renal disease have subsided following the withdrawal of immunosuppressive agents and simultaneous treatment with ganciclovir. Although there is no direct proof that CMV infection was responsible for the development of immunotactoid glomerulopathy, the circumstantial evidence in this patient strongly suggests that these two disease were temporally linked. To our knowledge, the association between CMV infection and immunotactoid glomerulopathy has not been documented previously.

Role of a basement membrane glycoprotein in anti-tubular basement membrane nephritis.

Tubulointerstitial nephritis antigen (TIN antigen) is a basement membrane component which is recognized by human autoantibodies in TIN and has been shown to induce TIN in Brown Norway (BN) rats. Detectable by immunofluorescent microscopy, TIN antigen reacts with monoclonal, polyclonal, and human autoantibodies in basement membranes of kidney cortex, small intestine, skin and cornea. Specific sites of TIN antigen within kidney cortex include basement membranes of proximal tubules, distal tubules, Bowman's capsule and peritubular capillaries, with highest concentration in proximal tubular basement membrane (TBM). TIN antigen is also present in interstitium between tubules and in the periarterial sheath, but not in glomerular basement membrane or mesangial matrix. Immunoblotting of TIN antigen isolated from rabbit TBM reveals a major 58 kDa component with minor components of 300 kDa, 175 kDa, 160 kDa, 100 kDa and 50 kDa. Partial protein sequence analysis indicates that 58 kDa TIN antigen represents a newly defined glycoprotein. The structural relationships between various molecular weight forms are currently being investigated. High molecular weight (HMW) forms of TIN antigen, consisting of a mixture of 300 kDa, 175 kDa and 160 kDa forms, are more efficient than low molecular weight (LMW) forms (58 kDa and 50 kDa forms) in inducing TIN in BN rats. The resultant antibody specificity of rats injected with either HMW TIN antigen or LMW TIN antigen is identical as determined by immunofluorescent microscopy and Western analysis. Higher antibody titers and greater amounts of kidney-bound IgG are found in the HMW TIN antigen-immunized animals. TIN antigen is the primary target of anti-TBM antibodies in human and experimental immunologically-mediated anti-TBM nephritis.

Septate gallbladder with cholelithiasis: a cause of chronic abdominal pain in a 6-year-old child.

This report describes the case of a 6-year-old girl with septate gallbladder and cholelithiasis without cholecystitis, an uncommon condition associated with chronic abdominal pain. The absence of smooth muscle components within the gallbladder septae supports an embryogenic abnormality that may have occurred early during the maturation of the gallbladder lumen. In concert with other predisposing factors, the septa may have induced gallstones and, thus, the patient's symptoms. Although rare, gallbladder abnormalities may cause abdominal pain in children and should be included in the differential diagnosis. Early ultrasound should be obtained as part of a workup if gallbladder abnormalities are suspected. Elective cholecystectomy is curative.

Detection of metastatic neuroblastoma in bone marrow biopsy specimens with an antibody to neuron-specific enolase.

To verify the practical utility of immunohistochemical analysis of bone marrow biopsy specimens in patients with neuroblastoma, we compared the results of routine histologic examination of 68 specimens with the results of immunohistochemical detection of tumor cells using an antibody to neuron-specific enolase (NSE). A commercially available polyclonal antibody to this enolase isoform consistently reacted with the neoplastic cells in biopsy specimens with histologic features diagnostic of (24 specimens) or suspicious for (one specimen) metastatic neuroblastoma. Immunohistochemical double-staining techniques documented that the NSE-positive neoplastic cells also reacted with antibodies to chromogranin and synaptophysin. Notably, anti-NSE detected small foci of metastatic neuroblastoma in two of 43 biopsy specimens that showed no evidence of metastatic tumor in the initial histologic sections. Rare NSE-reactive hematopoietic cells were present in approximately a third of the specimens with and those without neuroblastoma and were easily distinguished from metastatic tumor by morphologic examination. We conclude that this antibody to NSE consistently detects neuroblastoma cells in routinely processed bone marrow specimens, including small foci of tumor cells not evident in initial histologic sections.

Identification of lymphohemopoietic cells in the kidneys of normal rats.

Recently developed monoclonal antibodies against rat lymphohematopoietic cells provide ideal probes for study of the role of the cellular immune system in experimental renal disease. Techniques for optimal and reliable labeling of cells present within the glomeruli have not yet been established. In this study it is shown that a small number of lymphoid and mononuclear cells can be identified within normal rat glomeruli present on frozen kidney sections (4 mu) when indirectly stained with monoclonal antibody W3/13, W3/25, OX1, OX3, or OX8 with the use of sequential incubations with F(ab')2 fragments of 2 fluorochrome-labeled antibodies, the nuclear stain ethidium bromide, and p-phenylenediamine added to retard fluorescence quenching. Cell counts showed good correlation with those obtained with the use of intact glomeruli isolated simultaneously from the same kidneys (r = 0.95 for saline-perfused kidneys; r = 0.99 for exsanguinated kidneys). Studies using isolated glomeruli pretreated with trypsin and DNAase failed to provide any advantage, because the enzymes did not enhance cellular reactivity with W3/13, OX8, or OX3, whereas the W3/25-reactive epitope was completely destroyed. It was only the OX1-reactive epitope which was enhanced by enzyme pretreatment. Thus, the described technique can accurately quantitate glomerular lymphohemopoietic cells on sections of frozen kidney and should provide a reliable method for the study of renal disease.