Renal dysfunction after total body irradiation: dose-effect relationship: in regard to Kal and van Kempen-Harteveld (Int J Radiat Oncol Biol Phys 2006;65:1228-1232).
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Humans↗
Biomedical subjects
Eric P Cohen
Publications and source records attributed to Eric P Cohen.
Young Scholars Award Lecture: Intratubular angiotensinogen in hypertension and kidney diseases.
Recent findings related to the renin-angiotensin system have provided a more elaborated understanding of the pathophysiology of hypertension and kidney diseases. These findings have led to unique concepts and issues regarding the intrarenal renin-angiotensin system. Angiotensinogen is the only known substrate for renin that is the rate-limiting enzyme of the renin-angiotensin system. Because the level of angiotensinogen in human beings is close to the Michaelis-Menten constant value for renin, changes in angiotensinogen levels can control the activity of the renin-angiotensin system, and its upregulation may lead to elevated angiotensin peptide levels and increases in blood pressure. Enhanced intrarenal angiotensinogen mRNA or protein levels or both have been observed in multiple models of hypertension including angiotensin II-dependent hypertensive rats, Dahl salt-sensitive hypertensive rats, and spontaneously hypertensive rats, as well as in kidney diseases including diabetic nephropathy, immunoglobulin A (IgA) nephropathy, and radiation nephropathy. Renal angiotensinogen is formed primarily in proximal tubular cells and is secreted into the tubular fluid. Urinary angiotensinogen excretion rates show a clear relationship to kidney angiotensin II contents and kidney angiotensinogen levels, suggesting that urinary angiotensinogen may serve as an index of the intrarenal renin-angiotensin system status. Establishment of concise and accurate methods to measure human angiotensinogen may allow clinical studies that would provide important information regarding the roles of intrarenal angiotensinogen in the development and progression of hypertension and kidney diseases.
Angiotensinogen↗
Arachidonic acid metabolites mediate the radiation-induced increase in glomerular albumin permeability.
Radiation-induced renal injury is characterized by proteinuria, hypertension, and progressive decline in renal function. We have previously shown that in vivo or in vitro irradiation of glomeruli with a single dose of radiation (9.5 Gy) increases glomerular albumin permeability (P(alb)) within 1 hr. The current studies tested the hypothesis that this early radiation-induced increase in P(alb) is caused by the release of arachidonic acid and by the generation of specific arachidonic acid metabolites. Glomeruli obtained from WAG/Rij/MCW rats and cultured rat glomerular epithelial and mesangial cells were studied after irradiation (9.5 Gy, single dose). Arachidonic acid release and eicosanoid synthesis by glomeruli or cultured glomerular cells were measured after irradiation, and the effect of inhibitors of phospholipase A2 (PLA2) and cyclooxygenase (COX) on the irradiation-induced increase in P(alb) was assessed. Arachidonic acid release was demonstrated within 10 mins of irradiation of isolated glomeruli and monolayer cultures of glomerular epithelial and mesangial cells. Prostaglandin F(2alpha) (PGF(2alpha)) and PGE2 release was increased after irradiation of isolated glomeruli. Blocking arachidonic acid release or COX activity before irradiation completely prevented the increase in P(alb). COX inhibition immediately after irradiation also diminished the radiation-induced increase in P(alb). We conclude that arachidonic acid and its COX metabolites play an essential role in the early cellular changes that lead to the radiation-induced increase in P(alb). Understanding of the early epigenetic effects of irradiation may lead to new intervention strategies against radiation-induced injury of normal tissues.
Albumins↗
BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients.
BACKGROUND: BK virus nephritis (BKVN) has emerged as an important cause of renal transplant failure. Quantified analysis of its timing and clinical course is generally lacking. We have thus quantified the timing, risk factors, evolution of renal function, and transplant graft outcome in renal transplant recipients with BKVN from our center. METHODS: A total of 41 cases of BKVN were diagnosed in 1001 renal and renal/pancreas transplant recipients. There were 2 groups: group I (N= 16), with diagnosis based on renal biopsy alone from January 1996 to August 2001, and group II (N= 25), with diagnosis based on quantitative blood BKV-PCR and biopsy from September 2001 to December 2003. The demographics, the clinical course, immunosuppressive therapy, renal function, and graft outcome were quantified. Donor, recipient, and transplant risk variables were studied using a univariate analysis. Actuarial graft survival was calculated. An immunosuppressive scale created to evaluate the degree of immunosuppression in these patients and its reduction after the diagnosis of BKVN. RESULTS: The median time from transplant to BKVN diagnosis was 318 days (range 48-1356). The actuarial graft survival in patients with BKVN at 6 months, 1, 3, and 5 years was 97%, 90%, 58%, and 47%. The corresponding values for those without BKVN were 94%, 92%, 83%, and 76%, respectively, P < 0.001. Graft loss occurred in 46% of patients. The rate of decline of renal function in group II (N= 25) patients in the 4 months preceding BKVN was rapid (4.8 mL/min/month) and this declined to 0.7 mL/min/month at 3 months' post-BKVN diagnosis, P= 0.004. In those who recovered, the time to stabilization of renal function was a median of 112 days. The immunosuppressive scale score was 7 units at the time of diagnosis of BKVN and decreased to 3.5 units at 3 months' post-BKVN. Reduction in the dose of calcineurin inhibitors but not the overall reduction in dose of immunosuppression correlated with recovery of renal function in these patients. CONCLUSION: BKVN is a relatively late complication of renal transplantation. Despite reduction in immunosuppression, graft loss occurred in 46% of patients. There was a steep decline in renal function in months preceding the diagnosis of BKVN, and reduction in calcineurin inhibitor dose, but not overall immunosuppression, correlated with stabilization of renal function.
Adult↗
BK virus-specific antibodies and BKV DNA in renal transplant recipients with BKV nephritis.
We evaluated twenty renal transplant subjects at various stages of BKV nephritis (BKVN) for BKV-specific IgG and IgM antibodies using ELISA technique and BKV-DNA using PCR. They were divided as early onset (n = 7), stabilizing (n = 3), resolved (n = 8) and late onset (n = 2) BKVN. BKV-specific antibodies and BKV-DNA were simultaneously determined. The mean BKV-specific IgG level in early onset and stabilizing BKVN were 64 and 39 EIA units, and were significantly lower than 138 EIA units seen in resolved BKVN, P = 0.007, P = 0.008. The mean BKV-specific IgM levels in stabilizing BKVN was higher than resolved BKVN (130 vs 51 EIA units), P = 0.006. Mean plasma BKV loads for each group were 955,925, 5642 and 42 copies/mL of plasma, respectively. Prospective study in six BKVN cases revealed mean IgG, IgM levels and BKV-DNA at the time of diagnosis of BKVN as 39, 110 EIA units and 586,758 copies/mL of plasma, respectively. After a mean period of 5.2 months, IgG level increased to 120 EIA units (p = 0.0058) and had no detectable viral copies in circulation. Recovery from BKVN and elimination of BKV is associated with the development of BKV-specific IgG antibodies and this provides insight into the role of humoral immunity to BKV in the pathogenesis of BKVN.
Adult↗
Hypercalcaemia from non-prescription vitamin A.
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Aged↗
Impact of angiotensin II type 2 receptor blockade on experimental radiation nephropathy.
In the rat, blockade of angiotensin II type 1 receptors diminishes the functional changes that occur after kidney irradiation. It has been hypothesized that some of the beneficial effects of angiotensin II type 1 blockers in renal disease are caused by a rise in angiotensin II that stimulates the angiotensin II type 2 receptor. If this hypothesis applied in this model, blockade of the type 2 receptor should exacerbate radiation nephropathy and/or counteract the beneficial effects of type 1 receptor blockade. To assess this hypothesis, rats were given total-body irradiation plus bone marrow transplantation and then treated for 12 weeks with a type 1 receptor blocker (L158,809), a type 2 blocker (PD123319), both blockers, or no blockers. Rats were assessed for renal function (proteinuria, hypertension, azotemia) and renal failure for up to 62 weeks. Contrary to the hypothesis, the type 2 blocker alone produced a temporary delay in the development of radiation nephropathy, and it substantially enhanced the efficacy of the type 1 blocker. This implies that both type 1 and type 2 angiotensin receptors need to be blocked to achieve the maximum level of prophylaxis of radiation nephropathy. We speculate that the beneficial effect of the angiotensin II type 2 receptor blocker is due to a reduction in radiation-induced renal cell proliferation or fibrosis.
Angiotensin II Type 1 Receptor Blockers↗
Successful treatment of radiation nephropathy with angiotensin II blockade.
PURPOSE: The aim of this report is to document the successful treatment of radiation nephropathy. METHODS: Clinical case report with statistical analysis of evolution of kidney function. RESULTS: A case of radiation nephropathy was found in a kidney transplant recipient whose kidney transplant had been irradiated with 750 cGy 23 years previously. Use of the angiotensin II blocker, losartan, was associated with significant stabilization of the kidney function. CONCLUSION: Radiation nephropathy can be successfully treated. Other normal-tissue radiation injuries may also be treatable.
Adult↗
Radiation nephropathy.
The pronounced radiosensitivity of renal tissue limits the total radiotherapeutic dose that can be applied safely to treatment volumes that include the kidneys. The incidence of clinical radiation nephropathy has increased with the use of total-body irradiation (TBI) in preparation for bone marrow transplantation and as a consequence of radionuclide therapies. The clinical presentation is azotemia, hypertension, and, disproportionately, severe anemia seen several months to years after irradiation that, if untreated, leads to renal failure. Structural features include mesangiolysis, sclerosis, tubular atrophy, and tubulointerstitial scarring. Similar changes are seen in a variety of experimental animal models. The classic view of radiation nephropathy being inevitable, progressive, and untreatable because of DNA damage-mediated cell loss at division has been replaced by a new paradigm in which radiation-induced injury involves not only direct cell kill but also involves complex and dynamic interactions between glomerular, tubular, and interstitial cells. These serve both as autocrine and as paracrine, if not endocrine, targets of biologic mediators that mediate nephron injury and repair. The renin angiotensin system (RAS) clearly is involved; multiple experimental studies have shown that antagonism of the RAS is beneficial, even when not initiated until weeks after irradiation. Recent findings suggest a similar benefit in clinical radiation nephropathy.
Animals↗
Humanized anti-CD20 monoclonal antibody (Rituximab) treatment for post-transplant lymphoproliferative disorder.
INTRODUCTION: Post-transplant lymphoproliferative disorders (PTLD) is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The treatment of PTLD includes reduction/withdrawal of immunosuppression and chemotherapy. This study reports our center experience with humanized monoclonal antibody against CD-20 (Rituximab) for the treatment of PTLD. MATERIAL AND METHODS: Eight cases of PTLD after solid organ transplantation [six kidney, one kidney/pancreas (KP) and one liver] occurred between September 1998 and October 2001. The mean time between transplant and the diagnosis of PTLD was 57.3 months (range 3 months to 10 yr). Five patients underwent cadaveric transplant, five males and six were Caucasians with mean age of 48 yr (range 20-67 yr). RESULTS: The clinical presentation was as follows: lymphadenopathy--5, gastrointestinal bleeding--2 and tonsillar enlargement--1. The diagnosis was made by a lymph node biopsy in five, a gastric ulcer biopsy in two and a tonsillar biopsy in one case. Six of them had polymorphous, two had monoclonal B-cell lymphoma, and all were positive for CD-20. Six were related to EBV, documented by latent membrane protein (LMP) or Epstein-Barr encoded RNA (EBER) staining. Immunosuppression at the time of PTLD diagnosis consisted of tacrolimus in six cases and cyclosporine A (CsA) in two with mycophenolate mofetil (MMF) and azathioprine--3 each and sirolimus--1. Rituximab was administered at a dose of 375 mg/m2 once a week for 4 wk. There were no side effects seen with this therapy. Immunosuppression was reduced in all patients. Complete remission was observed in seven cases (one required two courses). One patient who did not respond received chemotherapy. Patients were followed for a mean period of 22.5 months (range 10-45 months post-PTLD diagnosis. At the last follow-up all eight patients were alive, seven with a functioning graft and one on maintenance dialysis. Three of these patients had been in remission for more than 2.5 yr. CONCLUSION: Rituximab is an effective agent in the treatment of PTLD without the morbidity characteristic of chemotherapy. Chemotherapy should be reserved only for those refractory to Rituximab therapy.
Adult↗
Benefit of child-to-parent kidney donation.
Use of child-to-parent (CTP) kidney donation may be limited because of ethical concerns as well as doubts about its effectiveness. We used the United Network for Organ Sharing database to examine the effectiveness of CTP kidney donation compared with other types of living-related (LD) kidney donation and to cadaveric kidney donation. Data from 56 873 kidney transplants performed between 1988 and 1998 showed significantly greater transplant and patient survival for CTP kidney transplants compared with cadaveric kidney transplants. The average gain in kidney transplant half-life is 3.6 years for a CTP compared with a cadaveric kidney transplant, and it is estimated that this gain for the recipient far outweighs the 1 in 3000 risk of death to the donor associated with kidney donation. We conclude that CTP kidney donation should not be discouraged, and represents a useful source of transplantable kidneys.
Adult↗
Evolution of endpoints for renal transplant outcome.
Progressive improvement in short-term kidney transplant survival and reduction in acute rejection rates have restricted our ability to assess newer therapy. Past and present conventional endpoints, such as short-term graft survival and acute rejection rates, are no longer practical. This has prompted investigators to search for alternative endpoints. Long-term graft survival is an ideal endpoint. However, this requires a large cohort of patients with longer follow-up. A simpler approach would be to identify short-term markers, which can predict long-term survival. Short-term potential markers that can predict long-term survival are: clinical (renal function), histological (renal pathological markers) and immunological (anti-donor antibody, blood and urine cytokines). Post-transplant renal function estimated by serum creatinine, cystatin C and creatinine clearance within 1 year, and histological indices, as the Banff chronicity score, have the potential to predict long-term graft survival. Serum creatinine is limited as a marker by its variability based on recipient age, body weight, race and sex. Histological indices are limited, due to the invasive nature of evaluation. Post-transplant renal function and histological indices can be used potentially as a composite endpoint, in combination with conventional endpoints, such as graft loss, death and acute rejection. A practical approach for assessing newer therapies in future studies is to use composite endpoints, which combine conventional endpoints (graft loss, death, acute rejection) with newer endpoints (renal function, histological indices).
Creatinine↗
Rapid kidney allograft failure in patients with polyoma virus nephritis with prior treatment with antilymphocyte agents.
Interstitial nephritis owing to polyoma virus infection (PVi) mimics acute allograft rejection. The risk factors for graft failure associated with PVi are unknown. This prompted us to analyse the relationship between the use of antilymphocyte agents (ALA) and graft dysfunction in renal transplant recipients with PVi. Renal transplant recipients who were diagnosed to have PVi nephritis at the Medical College of Wisconsin were included in this study. PVi nephritis was confirmed by urine cytology and characteristic renal histological findings in a total of 14 cases. Other viruses were excluded by immunohistochemistry studies. Patients were divided into two groups: Group A (n = 7) received ALA (OKT3/ATGAM) as treatment for presumptive acute rejection and Group B (n = 7) did not receive ALA therapy. The progression of renal function (GFR) was estimated by a 100/ plasma creatinine and an actuarial kidney survival was estimated by the Kaplan-Meier method. The demographics (age, gender, race, retransplant and kidney versus. kidney/pancreas), prior treatment with steroids for presumptive acute rejection, and renal function at the time of PVi diagnosis were similar betwoen groups. The fall in GFR/month was 6 mL/min/month with prior ALA therapy compared with 1 mL/min/month in those who did not receive ALA, p = 0.002. All seven grafts were lost in the ALA group compared with only two of seven grafts in the other group, p = 0.005. The use of ALA was associated with a rapid fall in GFR and graft failure in patients with PVi nephritis. Careful diagnosis of PVi is warranted in renal allograft recipients prior to initiating ALA therapy.
Analysis of Variance↗
The renin-angiotensin system in experimental radiation nephropathy.
Irradiation of the kidneys is followed by a well-defined sequence of changes leading eventually to kidney failure. In the rat, inhibition of angiotensin-converting enzyme or blockade of angiotensin II receptors can prevent the structural and functional changes that occur after kidney irradiation. These interventions are particularly effective between 3 and 10 weeks after irradiation. However, in a series of studies with the rat model we failed to find any evidence that the renin-angiotensin system (RAS) is activated in the first 10 weeks after kidney irradiation. First, if the RAS was activated during this interval, one would expect hypertension followed by proteinuria and azotemia. However, hypertension is significant only at the end of this period and is preceded by significant proteinuria and azotemia. This evolution is not in favor of an obviously activated RAS during the 3- to 10-week postirradiation interval that is critical for interventions aimed at the RAS. Second, plasma renin activity and active plasma renin protein concentrations are not significantly increased over the first 10 weeks after irradiation. Third, whole-blood and intrarenal angiotensin II levels are not increased and may even be decreased over this interval. This last observation is particularly important because the assay used is sensitive enough to detect the effects of dietary salt manipulation. We hypothesize that even the normal activity of the RAS contributes to injury after kidney irradiation, possibly by supporting the proliferation of cells that carry potentially lethal radiation injuries.
Animals↗
Stenosis of the glomerulotubular neck.
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Animals↗
Retinoic acid exacerbates experimental radiation nephropathy.
Studies have shown that angiotensin-converting enzyme inhibitors and an angiotensin II receptor blocker can delay, but cannot reverse, the progression of experimentally induced radiation nephropathy. In an effort to find a method for reversing injury, three agents were tested in a rat model of radiation nephropathy. Pirfenidone (a phenyl-pyridone antifibrotic) and thiaproline (an inhibitor of collagen deposition) were not capable of retarding the development of radiation nephropathy. However, all-trans retinoic acid (an anti-inflammatory agent) exacerbated radiation nephropathy. We speculated that the detrimental effects of retinoic acid might be the result of stimulation of renal cell proliferation. However, retinoic acid had no effect on tubular or glomerular cell proliferation in normal animals and did not enhance radiation-induced proliferation. A recent report that retinoic acids inhibit nitric oxide production suggested an alternative mechanism, since inhibition of production of nitric oxide is known to exacerbate radiation nephropathy. Experiments demonstrated that retinoic acid exacerbated the radiation-induced drop in renal production of nitric oxide, suggesting that the detrimental effect of all-trans retinoic acid might be explained by inhibition of renal nitric oxide activity. Particularly in view of the recent clinical report of enhancement of radiation nephropathy by retinoic acid in patients receiving bone marrow transplantation, the combination of retinoic acid and renal irradiation should be carried out with great caution.
Animals↗
Angiotensin II blockade reduces radiation-induced proliferation in experimental radiation nephropathy.
Total-body irradiation or renal irradiation is followed by a well-defined sequence of changes in renal function leading eventually to renal failure. Previous studies in a rat model have shown that inhibition of angiotensin-converting enzyme or blockade of angiotensin II receptors can prevent the structural and functional changes that occur after renal irradiation, and that these interventions are particularly important between 3 and 10 weeks after irradiation. We have now shown that in the same rat model, total-body irradiation induces proliferation of renal tubular cells (i.e., an increase in the number of cells staining positive for proliferating cell nuclear antigen) within 5 weeks after irradiation. Treatment with an angiotensin II receptor blocker delays this radiation-induced tubular proliferation and decreases its magnitude. Renal radiation also induces proliferation of glomerular cells, but the relative increase in glomerular proliferation is not as great as that seen in renal tubular cells, and the increase is not delayed or decreased by treatment with an angiotensin II receptor blocker. We hypothesize that angiotensin II receptor blockers exert their beneficial effect in radiation nephropathy by delaying the proliferation (and hence the eventual mitotic death) of renal tubular cells that have been genetically crippled by radiation.
Angiotensin Receptor Antagonists↗