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V Nickeleit

Publications and source records attributed to V Nickeleit.

At least 19 recordsLinked to original sources
PubMed2007

The classification and treatment of antibody-mediated renal allograft injury: where do we stand?

Since the acceptance of the detection of C4d in allografts as a reliable tool to mark a humoral alloresponse, de novo antibody-induced graft injury has attracted much attention. Antibodies and B cells are the new frontier in transplantation. At this juncture carefully designed studies are critical in order to gain solid diagnostic, therapeutic, and prognostic knowledge about the role of antibodies in graft injury and to avoid any confusion and misconception. One prerequisite is the strict adherence to refined classification systems of renal transplant rejection that carefully split and categorize different phenotypes of humoral mediated graft damage and ideally also include information on anti-donor antibody specificity and titers. Sun and colleagues follow this concept and provide evidence that mixed cellular and antibody-mediated graft rejection can respond favorably to intensified immunosuppression with tacrolimus and mycophenolate mofetil. What will the future bring to treat rejection episodes with a dominant, co-dominant, or minor antibody response?

Graft Rejection↗
PubMed2006

Acute and chronic vascular rejection in nonhuman primate kidney transplantation.

A nonhuman primate (NHP) study was designed to evaluate in nonlife-supporting kidney allografts the progression from acute rejection with transplant endarteritis (TXA) to chronic rejection (CR) with sclerosing vasculopathy. Group G1 (n = 6) received high cyclosporine A (CsA) immunosuppression and showed neither TXA nor CR during 90 days post-transplantation. Group G2 (n = 6) received suboptimal CsA immunosuppression and showed severe TXA with graft loss within 46 days (median). Arterial intimal changes included infiltration of macrophages and T lymphocytes (CD3, CD4, CD8) with few myofibroblasts, abundant fibronectin/collagen IV, scant collagens I/III, high rate of cellular proliferation and no C4d accumulation along peritubular capillaries. Group G3 (n = 12) received suboptimal CsA and anti-rejection therapy (rabbit ATG + methylprednisolone + CsA) of TXA. Animals developed CR and lost grafts within 65 days (median). As compared to G2, the arterial intimal changes showed less macrophages and T lymphocytes, an increased number of myofibroblasts, abundant fibronectin/collagen IV and scar collagens I/III, C4d deposition along capillaries in 60% of animals and transplant glomerulopathy in 80% of animals. In conclusion, CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts, and progressive deposition of collagens in the intima. Our experimental design appears well suited to study events leading to CR.

Acute Disease↗
PubMed2006

Isolated donor specific alloantibody-mediated rejection after ABO compatible liver transplantation.

Antibody-mediated rejection (AMR) after liver transplantation is recognized in ABO incompatible and xeno-transplantation, but its role after ABO compatible liver transplantation is controversial. We report a case of ABO compatible liver transplantation that demonstrated clinical, serological and histological signs of AMR without evidence of concurrent acute cellular rejection. AMR with persistently high titers of circulating donor specific antibodies resulted in graft injury with initial centrilobular hepatocyte necrosis, fibroedematous portal expansion mimicking biliary tract outflow obstruction, ultimately resulting in extensive bridging fibrosis. Immunofluorescence microscopy demonstrated persistent, diffuse linear C4d deposits along sinusoids and central veins. Despite intense therapeutic intervention including plasmapheresis, IVIG and rituximab, AMR led to graft failure. We present evidence that an antibody-mediated alloresponse to an ABO compatible liver graft can cause significant graft injury independent of acute cellular rejection. AMR shows distinct histologic changes including a characteristic staining profile for C4d.

ABO Blood-Group System↗
PubMed2006

The fate of C4d positive kidney allografts lacking histological signs of acute rejection.

BACKGROUND: C4d deposits in renal transplants are known to be an independent risk factor of graft failure. The current analysis evaluates the impact of C4d deposits on graft function and survival in renal transplants without morphological signs of rejection. METHODS: We retrospectively analyzed diagnostic transplant biopsies performed due to allograft dysfunction from June 1994 to June 2001 at the University Hospital in Basel. STUDY GROUP: Grafts/patients with focal or diffuse positivity of C4d along peritubular capillaries; absence of morphological signs of acute cellular and/or humoral rejection; up to 3 year follow-up analysis post index biopsy. Patients treated with anti-rejection therapy or an increase in maintenance immunosuppression post biopsy (intervention group = IG) were compared to patients with unaltered immunosuppression (standard group = SG). RESULTS: Study group: 22 biopsies/patients out of 400 biopsies (5%) were included into the study, 17 in the SG and 5 in the IG. Patient survival (1-/3-years): SG: 100/94%, IG: 80/80%; graft survival censored for death (1-/3-years): SG: 82.5/68.8%, IG: 100/100%; serum creatinine (micromol/l) at index biopsy/1-year/3-years: SG: 221 +/- 70/231 +/- 103/245 +/- 124, IG: 217 +/- 100/143 +/- 28/177 +/- 55; acute rejection episodes within 1 year post index biopsy: SG: 4 (4 patients), IG: 1 (1 patient); all differences not significant. Lowest serum creatinine within 4 weeks post index biopsy (IG vs. SG): 108 +/- 25 vs. 181 +/- 61, p = 0.02. CONCLUSIONS: C4d positivity in kidney transplants lacking histological evidence of acute rejection is not associated with rapid functional graft deterioration, even in untreated cases. However, anti-rejection therapy results in the improvement of kidney function. Thus, even in grafts with normal histology, the detection of C4d in diagnostic biopsies can be interpreted as a sign of "smoldering" rejection that benefits from therapy.

Acute Disease↗
PubMed2004

Differentiating thrombotic microangiopathies induced by severe hypertension from anemia and thrombocytopenia seen in thrombotic thrombocytopenia purpura.

Thrombotic microangiopathy (TMA) is a recognized complication of malignant hypertension (HTN). Such patients have blood pressures > or = 200/140 mmHg but the condition is defined by the presence of papilledema and is frequently complicated by acute renal failure. Here we report two patients with severe HTN (systolic > or = 180 mmHg or diastolic > or = 120 mmHg), TMA, thrombocytopenia, renal failure, and, in one case, neurological changes (4 of 5 manifestations of the TTP pentad). A 50-year-old male with HTN presented with blurred vision, dizziness, headache, confusion, renal failure, and a TMA (PLT = 39 x 10(9)/L and LD = 2,781 normal <600 U/L). On presentation, BP was 214/133 mmHg and an ophthalmic exam demonstrated no papilledema. With HTN control over 7 days, his platelet count rebounded (220 x 10(9)/L), LD declined (1,730 U/L), and mental status improved. A 60-year-old female with diabetes, HTN, Lupus erythematosus, mild chronic anemia, and thrombocytopenia presented with abdominal pain, shortness of breath, renal failure, and a TMA (PLT = 83 x 10(9)/L and LD = 2,929 U/L). Blood pressures were 180-210/89-111 mmHg and ophthalmic exam demonstrated no papilledema. With HTN control over 8 days, her platelet count rebounded (147 x 10(9)/L), and LD declined (1,624 U/L). Although in both cases a diagnosis of TTP was considered because of overlap with the classic diagnostic pentad, neither received plasmapheresis. TTP is a diagnosis of exclusion, where there is no other likely diagnosis to explain the TMA. In cases of severe HTN (with or without papilledema), the diagnosis of TTP should be held in abeyance until the effect of HTN control can be assessed.

Anemia↗
PubMed2004

[Polyomavirus nephropathy: pathogenesis, morphological and clinical aspects].

The polyoma-BK-virus strain was said to be "in search" of a disease. The search is finally over. Since the mid 1990's, when new third generation immunosuppressive drug regimens were introduced into the routine management of renal allograft recipients, the polyoma-BK-virus (allograft) nephropathy (BKN) has gained increasing clinical interest. BKN is currently the most common infection affecting renal allografts with a prevalence of 1% up to 10% reported in various transplant centers world-wide. It can lead to chronic allograft dysfunction and eventual graft loss in more than 50% of cases (observed in some institutions). BKN is most likely caused by the reactivation of latent BK viruses which enter under sustained and intensive immunosuppression into a productive and lytic replicative cycle. BKN is typically limited to the kidney transplant. It is histologically defined by the presence of intranuclear viral inclusion bodies in tubular and parietal glomerular epithelial cells. Different variants of polyomavirus inclusion bodies (types 1 through 4) and adjunct techniques [immunohistochemistry, electron microscopy and polymerase chain reaction (PCR)] that are used for proper characterization are described. Virally induced severe tubular injury is the morphologic correlate for the clinically observed allograft dysfunction. Special emphasis is placed on the pathogenesis leading from latent to productive BK-Virus infections and on the clinical and pathophysiological significance of different histological stages of BKN. Risk factors promoting disease as well as clues to diagnose BKN and concurrent acute allograft rejection are discussed. The pathologist's role in patient management using the detection of polyomavirus inclusion bearing decoy cells in the urine, plasma PCR analyses, and graft biopsies is highlighted.

BK Virus↗
PubMed2003

[Primary renal synovial sarcoma. A new entity in the morphological spectrum of spindle cell renal tumors].

We report 2 primary renal synovial sarcoma. These tumors were formerly designated as embryonal cystic sarcoma of the kidney. Most cases are diagnosed between the ages of 20 and 50 years. Some cases show local recurrence after nephrectomy. On gross examination, tumors are large, partially necrotic, and usually contain cysts. Microscopically, tumors are characterized by monomorphic plump spindle cells. The cysts are lined by mitotically inactive epithelial cells without striking cellular atypia. The spindle cells were immunoreactive for EMA, CD56, and sometimes for CD99. They were non-reactive for desmin, actin, S 100, and cytokeratins. The cyst epithelium is cytokeratin positive. The presence of a SYT-SSX gene fusion resulting from the t(X;18) characteristic for synovial sarcoma was demonstrated by reverse transcriptase polymerase chain reaction in both tumors. Primary renal synovial sarcoma is a distinctive tumor entity, which should be considered in renal tumors consisting of spindle cells.

Adult↗
PubMed2002

[Dynamic and flexible classification of transplant rejection].

Different classification systems of renal allograft rejection are in use. Although, significant progress has been made with the introduction of the widely recognized Banff classification scheme, major problems remain unsolved. Minimal diagnostic threshold levels for tubulo-interstitial rejection are lacking. "Hyperacute, acute and chronic rejection or allograft nephropathy" are ill defined entities and thereby hamper rather than promote the communication between clinicians and pathologists and prevent a better understanding of pathophysiological events. Here, we propose a classification system of renal allograft rejection which is primarily based on well characterized morphological changes. All anatomical compartments of the renal cortex i.e., the tubulo-interstitial compartment, arteries and glomeruli, can be affected by rejection individually or in combination. In the subgroups only morphological changes known to be induced by rejection are considered. Such a classification system has, in our opinion, several major advantages. Every group and subgroup can easily be amended by "qualifiers" providing additional immunohistochemical and molecular-biological information as they are known today or become available in the future. As knowledge expands, qualifiers may be added or removed without fundamentally changing the entire classification scheme--making the system flexible and dynamic.

Graft Rejection↗
PubMed2001

A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy.

The chelator somatostatin analogue dota-D-phe(1)-tyr(3)-octreotide (DOTATOC), which is stably labeled with the beta-emitting radioisotope yttrium 90 ((90)Y), is used as internal radiotherapy for the treatment of patients with advanced neuroendocrine tumors. We report 5 patients who developed chronic renal failure, caused in 3 patients by biopsy-proven thrombotic microangiopathy (TMA). Twenty-nine patients (14 men, 15 women) with normal renal function before therapy were treated with divided intravenous doses of (90)Y-DOTATOC approximately 6 weeks apart (mean normalized cumulative dose, 165.4 +/- 36.4 mCi/m(2)). Twenty-two of 29 patients were administered a normalized cumulative dose of 200 mCi/m(2) without side effects. Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m(2), 5 patients (4 women, 1 man) developed renal failure. Increasing serum creatinine levels were observed within 3 months after the last (90)Y-DOTATOC injection. The evolution was rapidly progressive in 3 patients, resulting in end-stage renal failure within 6 months. The remaining 2 patients developed chronic renal insufficiency (mean serum creatinine level, 300 micromol/L an average 16 months after the end of treatment). Renal biopsies performed in 3 patients showed typical signs of TMA involving glomeruli, arterioles, and small arteries. Patients treated with high-dose (90)Y-DOTATOC internal radiotherapy (cumulative dose > 200 mCi/m(2)) are at high risk to develop severe renal failure caused by TMA lesions. The histopathologic lesions are identical to those found after external radiotherapy, which suggests a causal relationship between (90)Y-DOTATOC and renal TMA.

Biopsy↗
PubMed2001

Polyomavirus BK nephropathy in a kidney transplant recipient: critical issues of diagnosis and management.

Diagnosis of polyomavirus BK nephropathy and treatment by low-dose immunosuppression may be optimized by using surrogate markers, such as the detection of viral inclusion bearing cells in the urine and polyomavirus BK DNA in plasma by polymerase chain reaction. These markers were used prospectively in the management of a 44-year-old woman and led to the diagnosis of polyomavirus BK nephropathy at an early stage. The management was complicated by the concurrence of acute allograft rejection. Two treatment steps were initiated: antirejection therapy consisting of methylprednisolone for 3 days followed by lowering of the maintenance immunosuppression. This treatment resulted in a return of the serum creatinine concentration to the baseline of 1.6 mg/L, clearance of polyomavirus BK from plasma, and disappearance of viral inclusion bearing cells from the urine. After 2 months of stable allograft function, a control biopsy confirmed the resolution of polyomavirus BK nephropathy. Histologic signs of acute interstitial rejection were found and preemptively treated by methylprednisolone without altering the baseline regimen. Allograft function remained stable without evidence of recurrent polyomavirus BK nephropathy. This case shows the value of surrogate markers used in a prospective fashion for diagnosis and management of polyomavirus BK nephropathy with concurrent rejection.

Adult↗
PubMed2001

Coexistence of Fabry's disease and necrotizing and crescentic glomerulonephritis.

The coexistence of Fabry's disease, an X-linked hereditary disease, and other renal diseases, has rarely been described in the same patient. Combined Fabry's disease and pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) is hitherto unreported. We present the clinical and pathologic data of two patients with combined Fabry's disease and NCGN. Both patients presented with fevers of unknown origin and progressive renal insufficiency, however, lacked any other pathognomic signs of Fabry's disease such as acroparesthesias, dyshidrosis, and cutaneous angiokeratomas. The possible pathogenic mechanisms and causal relationship between the two disease processes are discussed.

Adult↗
PubMed2000

Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy.

BACKGROUND: Reactivation of polyomavirus type BK (BK virus) is increasingly recognized as a cause of severe renal-allograft dysfunction. Currently, patients at risk for nephropathy due to infection with the BK virus are identified by the presence of cells containing viral inclusion bodies ("decoy cells") in the urine or by biopsy of allograft tissue. METHODS: In a retrospective analysis, we performed polymerase-chain-reaction assays for BK virus DNA in plasma samples from 9 renal-allograft recipients with BK virus nephropathy; 41 renal-allograft recipients who did not have signs of nephropathy, 16 of whom had decoy cells in the urine; and as immunocompromised controls, 17 patients who had human immunodeficiency virus type 1 (HIV-1) infection (stage C3 according to the classification of the Centers for Disease Control and Prevention) and who had not undergone transplantation. RESULTS: In all nine patients with BK virus nephropathy, BK virus DNA was detected in the plasma at the time of the initial histologic diagnosis (a mean [+/-SD] of 46+/-28 weeks after transplantation) and during the course of histologically diagnosed, persistent BK virus disease. In three of the six patients with nephropathy who were studied serially after transplantation, BK virus DNA was initially undetectable but was detected 16 to 33 weeks before nephropathy became clinically evident and was confirmed by biopsy. Tests for BK virus DNA in plasma became negative and the nephropathy resolved after the doses of immunosuppressive drugs were decreased in two patients and after removal of the renal allograft in three patients. BK virus DNA was found in the plasma of only 2 of the 41 renal-allograft recipients who had no signs of nephropathy and in none of the patients with HIV-1 infection. CONCLUSIONS: Testing for BK virus DNA in plasma from renal-allograft recipients with use of the polymerase chain reaction is a sensitive and specific method for identifying viral nephropathy.

BK Virus↗
PubMed2000

BK-virus nephropathy in renal transplants-tubular necrosis, MHC-class II expression and rejection in a puzzling game.

We review BK-virus nephropathy (BKN) as a new complication that increasingly affects renal allografts and causes dysfunction. Since starting in 1996, we have seen 11 cases. Currently, the prevalence of BKN is 3% in our graft biopsies. The diagnosis can only be made histologically. The virus affects tubular epithelial cells that show characteristic intranuclear inclusion bodies. The major reason for impaired graft function and a possible way for viral particles to gain access to the blood via peritubular capillaries is necrosis of infected epithelial cells. BK-virus DNA in the plasma, which can be detected by PCR, is closely associated with nephropathy. BK-virus does not stimulate tubular MHC-class II expression as judged by immunofluorescence double labelling. The inflammatory response is inconsistent and the frequency of rejection episodes is not increased during disease. Clinical manifestation of viral nephropathy evolves in several stages. (i) Initial, asymptomatic and reversible activation of the virus, judged by the presence of inclusion bearing cells in the urine. (ii) High dose immunosuppressive drug regimens, often including tacrolimus. (iii) Tubular injury and viraemia as additional promoting conditions. BKN nephropathy was associated with graft loss in 45% of our patients. The remaining patients with persistent viral nephropathy showed renal dysfunction (serum creatinine levels on average 150% above baseline readings). Currently, no established antiviral therapy is available. We discuss attempts to lower immunosuppression as a means to control viral replication. We propose a diagnostic algorithm for screening and monitoring the disease.

Animals↗
PubMed1999

Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss.

BACKGROUND: Manifest polyomavirus (PV) renal graft infection is a rare complication. We diagnosed 5 cases among 70 kidney recipients undergoing transplants since December 1995; however, there were no cases at our institution before December 1995. METHOD: To identify risk factors promoting manifest PV graft infection, we compared those 5 patients with kidney recipients who had signs of PV replication but no manifest graft infection (n=23, control group). PV replication was judged by the presence of intranuclear inclusion cells in the urine. RESULTS: Before the infection, five of five patients had recurrent rejection episodes. All were switched from cyclosporine A to high dose tacrolimus as rescue therapy. Infection was diagnosed histologically 9+/-2 months posttransplantation; it persisted and led to graft loss in four of five patients. In control patients, graft function was stable, 1 of 23 patients were switched to tacrolimus as rescue therapy, and graft loss occurred in 4 of 23 patients. CONCLUSION: Recurrent rejection episodes and high dose immunosuppressive therapy, including tacrolimus, are risk factors for manifest PV kidney graft infection, which has an ominous prognosis.

Graft Rejection↗