[Acute renal failure and rare severe complication of systemic steroid treatment in a 73-year-old woman]. / Akutes Nierenversagen und seltene schwere Komplikation einer systemischen Steroidtherapie bei einer 73­Jährigen.

This article reports about a 73-year-old woman of Bosnian descent who presented with acute renal failure. A renal biopsy was diagnostic for a postinfect necrotizing and extracapillary proliferative glomerulonephritis. The patient reported a febrile infection fever 2 weeks previously. The diagnostics did not reveal any indications of an ongoing infection. The glomerulonephritis responded to treatment with systemic steroids. The patient was readmitted to hospital 6 weeeks later in a severely ill condition. A gastric biopsy revealed a Strongyloides stercoralis infestation. Due to the systemic steroid therapy the patient had developed a so-called hyperinfection syndrome and died despite treatment on the intensive care unit. This case illustrates the need for awareness of this rare parasitosis, particularly in patients from endemic areas. A likely causal relationship with the glomerulonephritis is discussed and an overview of the diagnostics, course of the disease and treatment of this parasitosis is given.

[Antifreeze poisoning : The case of a patient with repeated ethylene glycol poisoning]. / Intoxikation nach Frostschutzmittelaufnahme : Der Fall eines Patienten nach wiederholter Ethylenglykolintoxikation.

Ethylene glycol poisoning of incidental or suicidal intention can cause life-threatening metabolic acidosis, diverse secondary damage, and even lead to death. Beside hemodialysis effective therapy consists of the administration of fomepizole and ethanol. We describe a patient after repeated ethylene glycol poisoning with high anion gap metabolic acidosis and acute renal failure. Using hemodialysis, with dialysate containing a specific amount of ethanol, and intravenous ethanol administration we were able to prevent severe secondary organ damage.

The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.

The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials.

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology.

The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.

Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC).

The immunological checkpoints of programmed death 1 and its ligand (PD-L1) are currently in focus as novel therapeutic targets in renal cell carcinoma (RCC). The aim of this study was to evaluate the prognostic association of PD-L1 expression in clear cell (cc) RCC with clinical parameters, tumor aggressiveness and overall survival (OS). Patients who underwent renal surgery due to RCC between 1994 and 2003 were retrospectively evaluated. Tumor specimens were analyzed for PD-L1 expression by immunohistochemistry. One hundred and seventy-seven ccRCC patients were eligible for analysis, in which 140 (79.1 %) were negative and 37 (20.9 %) were positive for PD-L1 expression. PD-L1 positivity was associated with female gender (p = 0.001), lymph node metastasis (p = 0.004), distant metastasis (p = 0.002), higher AJCC stage (p = 0.004), as well as advanced disease (pT3/4 and/or N+ and/or M1) (p < 0.001). Kaplan-Meier analysis revealed a significantly diminished 5- and 10-year overall survival of 46.7 and 28.3 % for PD-L1(+) compared to PD-L1(-) tumors with 66 and 53.4 % (p = 0.005), respectively. Univariate analysis showed a significant negative association of OS with PD-L1 positivity [p = 0.005; HR: 2 (95 % CI 1.2-3.3)], even though PD-L1 positivity only tends to predict independently the OS using multivariate analyses [p = 0.066; HR: 1.6 (95 % CI 0.98-2.7)]. PD-L1 expression in ccRCC is associated with parameters of aggressiveness, as well as with poor OS, even though PD-L1 status was not identified as a significant independent prognostic parameter. However, further studies in larger cohorts are warranted.

Banff Borderline Changes Suspicious for Acute T Cell-Mediated Rejection: Where Do We Stand?

The definition of Banff Borderline became ambiguous when the Banff 2005 consensus modified the lower threshold from i1t1 (10-25% interstitial inflammation with mild tubulitis) to i0t1 (0-10% interstitial inflammation with mild tubulitis). We conducted a worldwide survey among members of the Renal Pathology Society about their approach to this diagnostic category. A web-based survey was sent out to all 503 current members (153 respondents). A database search yielded which threshold for Banff i was applied in the most influential manuscripts about Borderline. Among the 139 nephropathologists using the Borderline category, 67% use the Banff 1997 definition, requiring Banff i1. Thirty-seven percent admitted to sometimes exaggerating Banff i in the presence of tubulitis, to reach a diagnosis of Borderline. Forty-eight percent were dissatisfied with the definition of Borderline. The majority of the most influential manuscripts used the 1997 definition, contrary to the current one. There is considerable dissatisfaction with Borderline, and practice in Banff i thresholds is variable. Until additional studies inform a revision, we suggest leaving it to each pathologist's discretion whether to use i0 or i1 as the minimal threshold. In order to avoid future ambiguity, a web-based synopsis of all scattered current Banff definitions and rules should be created.

Role of immunohistochemistry and fluorescence in-situ hybridization (FISH) in the diagnosis of spindle and round cell tumors of the kidney.

UNLABELLED: Spindle cell/mesenchymal tumors of the kidney are rare. The diagnosis is supported mainly by the application of ancillary techniques such as immunohistochemistry (IH) and in-situ hybridization (FISH). An accurate diagnosis is essential because early management by complete resection and adjuvant chemotherapy improves the prognosis dramatically. Synovial sarcoma and primitive neuroectodermal tumor/Ewing sarcoma are infrequent malignancies which usually present in soft tissues but rarely in the kidney. The challenge for the pathologists is to histologically differentiate between different types of sarcomas such as PNET/Ewing's sarcoma, sarcomatous dedifferentiated renal cell carcinoma, metastasis, non-Hodgkin's lymphoma, nephroblastoma and angiomyolipoma. METHODS: We report from our experience six exemplary rare cases that presented in the kidney as spindle/round cell tumors. RESULTS: We have arrived at the accurate diagnosis after performing a large panel of IH and FISH. CONCLUSION: In summary we advise an immunohistochemical panel for round/spindle cell tumors of the kidney and for unclear cases we advise to add (FISH) to get the correct diagnosis, as they are completely different regarding surgical approach and post-operative adjuvant therapy.

eEOC-mediated modulation of endothelial autophagy, senescence, and EnMT in murine diabetic nephropathy.

Diabetic nephropathy is the most frequent single cause of end-stage renal disease in our society. Microvascular damage is a key event in diabetes-associated organ malfunction. Early endothelial outgrowth cells (eEOCs) act protective in murine acute kidney injury. The aim of the present study was to analyze consequences of eEOC treatment of murine diabetic nephropathy with special attention on endothelial-to-mesenchymal transdifferentiation, autophagy, senescence, and apoptosis. Male C57/Bl6N mice (8-12 wk old) were treated with streptozotocin for 5 consecutive days. Animals were injected with untreated or bone morphogenetic protein (BMP)-5-pretreated syngeneic murine eEOCs on days 2 and 5 after the last streptozotocin administration. Four, eight, and twelve weeks later, animals were analyzed for renal function, proteinuria, interstitial fibrosis, endothelial-to-mesenchymal transition, endothelial autophagy, and senescence. In addition, cultured mature murine endothelial cells were investigated for autophagy, senescence, and apoptosis in the presence of glycated collagen. Diabetes-associated renal dysfunction (4 and 8 wk) and proteinuria (8 wk) were partly preserved by systemic cell treatment. At 8 wk, antiproteinuric effects were even more pronounced after the injection of BMP-5-pretreated cells. The latter also decreased mesenchymal transdifferentiation of the endothelium. At 8 wk, intrarenal endothelial autophagy (BMP-5-treated cells) and senescence (native and BMP-5-treated cells) were reduced. Autophagy and senescence in/of cultured mature endothelial cells were dramatically reduced by eEOC supernatant (native and BMP-5). Endothelial apoptosis decreased after incubation with eEOC medium (native and BMP-5). eEOCs act protective in diabetic nephropathy, and such effects are significantly stimulated by BMP-5. The cells modulate endothelial senescence, autophagy, and apoptosis in a protective manner. Thus, the renal endothelium could serve as a therapeutic target in diabetes-associated kidney dysfunction.

The effect of mTOR-inhibition on NF-κB activity in kidney ischemia-reperfusion injury in mice.

Kidney ischemia-reperfusion injury (IRI) is associated with a robust inflammatory response, which is regulated by nuclear factor-kappaB (NF-κB), mainly its heterodimeric form p65/p50. Considering immunomodulatory properties of mammalian target of rapamycin (mTOR) inhibitors, the effect of everolimus on NF-κB activation in kidney IRI was determined in this study. IRI was induced in C57/BL6 mice by clamping both renal pedicles for 45 minutes. Application of everolimus (0.25 mg/kg bw subcutaneously daily) was started one day before IRI induction. Both everolimus-treated and nontreated mice were sacrificed at several times starting at 30 minutes and finishing on day 7 after IRI induction. The NF-κB activity, proinflammatory cytokines IL-1ß, TNF-α, and anti-inflammatory cytokine IL-10 production were determined in kidneys. Compared with nontreated animals, everolimus-treated animals showed significantly increased TNF-α (2741.6 ± 201.72 pg/mg; 1925 ± 185.81 pg/mg, P < .05) and IL-1ß (11.47 ± 1.2 pg/mg; 4.3 ± 0.13 pg/mg, P < .01) production on day 2 after IRI induction accompanied by significantly greater NF-κB/DNA binding activity and p65 nuclear expression (P < .01). Two hours after IRI induction, everolimus-treated animals showed significantly increased IL-1ß mRNA expression (P < .05) followed by increased IL-1ß protein concentrations when compared with nontreated animals measured 6 hours after IRI induction (11.71 ± 1.5 pg/mg; 7.5 ± 1.11 pg/mg, P < .01). Both experimental groups showed increased NF-κB/DNA binding activity at 7 days after IRI induction. Significantly increased nuclear p65 expression was measured in nontreated animals (P < .01), whereas everolimus-treated hosts showed significantly increased nuclear RelB expression (P < .01). These data suggested that everolimus potentiated innate immunity in the early phase of IRI, stimulating the production of NF-κB-driven proinflammatory cytokines such as TNF-α and IL-1ß. The NF-κB activity was potentiated under m-TOR inhibition during kidney IRI, implicating a possible beneficial role of alternative NF-κB activation during the repair phase.

[Partial nephrectomy after neoadjuvant administration of sunitinib facilitates preservation of a solitary kidney]. / Partielle Nephrektomie nach neoadjuvanter Therapie mit Sunitinib ermöglicht den Nierenerhalt bei Einzelniere.

We report on a 66-year-old female patient, presenting with a renal mass of 7.1 cm diameter on CT scan indicative of malignancy in the left solitary kidney. At first, the attempt at an open partial nephrectomy was undertaken. The intraoperative findings, however, did not allow for a kidney-preserving surgical procedure, mostly due to the close proximity of the tumour to the hilar vessels. The histopathology obtained during the procedure showed a clear cell renal cell carcinoma. Thus, systemic therapy with sunitinib over a period of 70 days (2 cycles/50 mg p. d.) was initiated. The subsequent CT scan showed shrinkage of the tumour with a partial response according to RECIST criteria (response evaluation criteria in solid tumours) of 32%. After discontinuation of sunitinib therapy, a partial nephrectomy was possible without complications. Postoperative follow-up was uneventful. The glomerular filtration rate before discharge was stable at 48 mL/min. The final tumour pathology showed a clear cell renal cell carcinoma - pTNM: pT1b, pNx, G2, R0.

[Acute tubulointerstitial nephritis as hyperergic reaction of the kidneys]. / Akute tubulointerstitielle Nephritis als hypererge Reaktion der Niere.

Acute tubulointerstitial nephritis was formerly only observed during the early phase of infections. With the emergence of antibiotics this disease became a rarity. In contrast the importance of drug-associated acute tubulointerstitial nephritis grew in importance and is now the most common form and expression of a hyperergic reaction of the kidneys. Acute tubulointerstitial nephritis occurs as a third form in cases of systemic autoimmune diseases, e.g., in idiopathic tubulointerstitial nephritis or within the scope of Sjögrens syndrome with distal tubular acidosis. The common symptoms of the drug-induced form are fever, side pain, microhematuria or macrohematuria and a mostly sharp increase in creatinine levels but to a greatly differing extent. Histologically, there is interstitial edema and interstitial lymphocyte-rich infiltration with tubulitis. The symptoms can be subclinical or even non-existent. In most case remission occurs, sometimes only partial remission or transformation to chronic interstitial nephritis. Risk factors are for example delayed diagnosis, recurrent episodes and the accompanying use of analgesics. The more acute and intense the clinical symptoms are, the earlier the diagnosis and therefore the better the prognosis. A temporary steroid treatment can promote regression.

Prognostic and diagnostic relevance of hypermethylated in cancer 1 (HIC1) CpG island methylation in renal cell carcinoma.

The tumour suppressor gene hypermethylated in cancer 1 (HIC1) is a transcriptional repressor, which functionally cooperates with p53. Loss of HIC1 function is associated with the development of various tumor entities. The aim of this study was to elucidate the relevance of CpG island (CGI) methylation of HIC1 in renal cell carcinoma (RCC). DNA methylation of HIC1 was analysed in a total of 98 tumor and 70 tumor adjacent normal specimens. After conducting bisulfite conversion, relative methylation levels were quantitated using pyrosequencing. Relative methylation values were compared for paired tumor and normal specimen and for correlation with clinico-pathologic and follow-up data of patients. Tumor-specific hypermethylation could not be detected for the subregion of the HIC1 - CGI analyzed in this study. Comparing the level of methylation in tumors to clinicopathological data solely, patients without lymph node metastases demonstrated a higher level of methylation compared to patients with lymph node metastases (p=0.030). Patients recurrence-free survival (p=0.0074) both in univariate as well as bivariate cox regression analysis. This study identifies HIC1 hypermethylation in tumors as an independent predictor of reduced recurrence-free survival, which fits into our current understanding of hypermethylated HIC1 being a marker for poor prognosis. Therefore, HIC1 - CGI methylation could be a candidate marker to improve individualized therapy and risk stratification.

The hormone melatonin stimulates renoprotective effects of "early outgrowth" endothelial progenitor cells in acute ischemic kidney injury.

Endothelial progenitor cells (EPCs) protect the kidney from acute ischemic injury. The aim of this study was to analyze whether pretreatment of murine "early outgrowth" EPCs (eEPCs) with the hormone melatonin increases the cells' renoprotective effects in the setting of murine acute ischemic renal failure. Male (8-12 wk old) C57Bl/6N mice were subjected to unilateral ischemia-reperfusion injury postuninephrectomy (40 min). Postischemic animals were injected with either 0.5×10(6) untreated syngeneic murine eEPCs or with cells, pretreated with melatonin for 1 h. Injections were performed shortly after reperfusion of the kidney. While animals injected with untreated cells developed acute renal failure, eEPC pretreatment with melatonin dramatically improved renoprotective actions of the cells. These effects were completely reversed after cell pretreatment with melatonin and the MT-1/-2 antagonist luzindole. In vitro analysis revealed that melatonin reduced the amount of tumor growth factor-ß-induced eEPC apoptosis/necrosis. Secretion of vascular endothelial growth factor by the cells was markedly stimulated by the hormone. In addition, migratory activity of eEPCs was enhanced by melatonin and supernatant from melatonin-treated eEPCs stimulated migration of cultured mature endothelial cells. In summary, melatonin was identified as a new agonist of eEPCs in acute ischemic kidney injury.

[Renal side effects of long-term lithium therapy]. / Nephrologische Nebenwirkungen einer Langzeittherapie mit Lithium.

Lithium is widely used in the treatment of bipolar disorders. Long-term administration of lithium often leads to side effects concerning the subjects: nephrology, endocrinology and surgery. This review emphasizes nephrotoxicity.Lithium treatment may disturb responsiveness to antidiuretic hormone (ADH), causing a nephrogenic diabetes insipidus. Furthermore long-term lithium therapy may trigger hyperparathyreoidism with hypercalcemia and chronic interstitial nephritis with development of microcysts. Long-term patients have an increased risk to develop impaired renal function. Lithium-induced endstage renal disease is rare. Termination of lithium treatment may decrease the risk of progression.To ensure security of lithium treatment regular controls of urine osmolarity, lithium-, creatinine- , thyroid stimulating hormone- and calcium-levels are essential. Patients with decreased renal function should be referred to a specialist early.

[BK virus nephropathy after kidney transplantation]. / BK-Virusnephropathie nach Nierentransplantation.

JC and BK viruses are strains of the polyomavirus group with pathogenic potential in humans. BK is the most frequent pathogenic agent of polyomavirus nephropathy (BKVN) in kidney transplant patients, which is only exceptionally caused by JC virus. Asymptomatic BK virus infection is often acquired in childhood and the virus persists in urothelium and kidneys of healthy individuals, where it can be reactivated under immunosuppression. Up to 10% of transplanted kidneys are affected by BKVN, while the risk of transplant failure due to BKVN exceeds 50% in some publications. In kidney biopsies BKVN leads to tubulointerstitial nephritis, which may be difficult to distinguish from acute cellular rejection without additional use of immunohistochemistry for a polyomavirus antigen. Typical hallmarks of BKVN include cytopathic effects caused by the virus with cell lysis, denudation of tubular basement membranes and nuclear inclusion bodies. An early diagnosis is essential for transplant survival, making screening of blood and urine for BK virus after kidney transplantation part of the standard care of renal transplant patients today. In the case of significant viremia or biopsy-proven BKVN immunosuppression is reduced to allow clearing of the virus.

Biopsy-diagnosed renal disease in patients after transplantation of other organs and tissues.

Renal function deteriorates in about half of patients undergoing other transplants. We report the results of 105 renal biopsies from 101 nonrenal transplant recipients (bone marrow 14, liver 41, lung 30, heart 20). Biopsy indications were protracted acute renal failure (9%), creatinine increases (83%), heavy proteinuria (22%), or renal insufficiency before re-transplantation (9%). Histological findings other than nonspecific chronic changes, hypertension-related damage, and signs of chronic CNI toxicity included primary glomerular disease (17%), mostly after liver transplantation (21%) or after bone marrow transplantation (29%), and thrombotic microangiopathy (TMA) namely (10%). TMA had the most serious impact on the clinical course. Besides severe hypertension, one TMA patient died of cerebral hemorrhage, 5 had hemolytic-uremic syndrome, and 6 rapidly developed end-stage renal failure. TMA patients had the shortest kidney survival post-biopsy and, together with patients with acute tubular injury, the shortest kidney and patient survival since transplantation. Nine TMA patients had received CNI, 3 of them concomitantly received an mTOR-inhibitor. CNI toxicity is implicated in most patients with renal failure after transplant of other organs and may play a role in the development of TMA, the most serious complication. However, decreased renal function should not be routinely ascribed to CNI.