Hemophagocytic lymphohistiocytosis and thrombotic microangiopathy after parvovirus B19 infection and renal transplantation: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease characterized by hyperactivation of the immune system that causes hypercytokinemia and potentially multi organ failure. HLH can occur in patients with underlying rheumatic or autoinflammatory disorders. Additionally, HLH can develop in patients during infections or malignancies without a known genetic predisposition. CASE PRESENTATION: We herein report a patient, who presented with fever, both acute kidney and liver injury, anemia, thrombocytopenia and HSV stomatitis. HLH was diagnosed based on clinical criteria and qPCR revealed an acute parvovirus B19 infection as potential underlying infectious trigger. Treatment was started with both IVIG and dexamethasone. Subsequently, kidney biopsy demonstrated TMA. CONCLUSIONS: In rare cases both HLH and aHUS can occur simultaneously in a patient as a consequence of viral infections. Insights from this unusual case might help physicians understand this complex symptom constellation.

COVID-19 effects on the kidney.

Apart from pulmonary disease, acute kidney injury (AKI) is one of the most frequent and most severe organ complications in severe coronavirus disease 2019 (COVID-19). The SARS-CoV­2 virus has been detected in renal tissue. Patients with chronic kidney disease (CKD) before and on dialysis and specifically renal transplant patients represent a particularly vulnerable population. The increasing number of COVID-19 infected patients with renal involvement led to an evolving interest in the analysis of its pathophysiology, morphology and modes of virus detection in the kidney. Meanwhile, there are ample data from several autopsy and kidney biopsy studies that differ in the quantity of cases as well as in their quality. While the detection of SARS-CoV­2 RNA in the kidney leads to reproducible results, the use of electron microscopy for visualisation of the virus is difficult and currently critically discussed due to various artefacts. The exact contribution of indirect or direct effects on the kidney in COVID-19 are not yet known and are currently the focus of intensive research.

[COVID-19 effects on the kidney]. / COVID-19-Auswirkungen auf die Niere.

Apart from pulmonary disease, acute kidney injury (AKI) is one of the most frequent and most severe organ complications in severe coronavirus disease 2019 (COVID-19). The SARS-CoV­2 virus has been detected in renal tissue. Patients with chronic kidney disease (CKD) before and on dialysis and specifically renal transplant patients represent a particularly vulnerable population. The increasing number of COVID-19 infected patients with renal involvement led to an evolving interest in the analysis of its pathophysiology, morphology and modes of virus detection in the kidney. Meanwhile, there are ample data from several autopsy and kidney biopsy studies that differ in the quantity of cases as well as in their quality. While the detection of SARS-CoV­2 RNA in the kidney leads to reproducible results, the use of electron microscopy for visualisation of the virus is difficult and currently critically discussed due to various artefacts. The exact contribution of indirect or direct effects on the kidney in COVID-19 are not yet known and are currently the focus of intensive research.

[Membranoproliferative glomerulonephritis and C3 glomerulopathy]. / Membranoproliferative Glomerulonephritis und C3­Glomerulopathie.

Based on an increasingly better pathophysiological understanding over the last 10 years, in 2010 a new classification of glomerulonephritis with dominant or codominant C3 deposits was introduced and the predominant subgoup was termed C3 glomerulopathy (C3G). In the current classification, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) form a disease spectrum which is very heterogeneous in terms of pathophysiology and the clinical course. Recent evidence suggests that IC-MPGN and C3G share more pathophysiological aspects with respect to secondary causes, autoantibodies and genetic aspects than had been suggested with the creation of the new classification. Knowledge of the underlying pathophysiology is important for guiding the diagnostic steps for clarification of secondary causes. Comprehensive complement analysis, accompanied by antibody screening and genetic analysis, should be consistently carried out. Although not systematically validated in clinical trials, the published evidence provides a robust foundation for the use of available treatment approaches for these diseases that are often rapidly progressive and often return after renal transplantation.

[(Immuno­)Pathology of drug side effects in the kidney]. / (Immun­)Pathologie von Medikamentennebenwirkungen in der Niere.

Nephrotoxicity or renal side effects of drugs are frequent and may vary in their clinical presentation. Various types of acute and chronic kidney disease are known to develop as a consequence or side effect of a long list of drugs with nephrotoxicity most commonly being associated with injury in the tubulointerstitial compartment. In addition, drug-induced glomerular and vascular disease have also been reported, either as the result of direct cellular injury or immune-mediated injury to glomerular or endothelial cells. From a clinical point of view it is important to recognize such drug-induced nephropathies early in order to prevent or adequately treat them to favour kidney recovery and to avoid long-lasting negative consequences for kidney function.This article will focus on the typical morphology and pathogenesis of some frequent drug-induced renal diseases.

Macrophage polarisation changes within the time between diagnostic biopsy and tumour resection in oral squamous cell carcinomas--an immunohistochemical study.

BACKGROUND: The prognosis of solid malignancies has been shown to depend on immunological parameters, such as macrophage polarisation (M1/M2). Recently, it was reported that preoperative oral surgery leads to a worsening of oral squamous cell carcinomas (OSCC) prognosis. Diagnostic incision biopsies are oral surgery procedures that might lead to healing-associated M2 macrophage polarisation with a potential negative influence on tumour biology. No studies have compared macrophage polarisation in OSCC biopsies and tumour specimens. METHODS: Preoperative diagnostic incision biopsies (n=25) and tumour resection specimens (n=34) of T1/T2 OSCC were processed for immunohistochemistry to detect CD68-, CD11c-, CD163- and MRC1-positive cells. Samples were digitised using whole-slide imaging, and the expression of macrophage markers was quantitatively analysed. RESULTS: Carcinoma tissues obtained during OSCC tumour resections showed a significantly (P<0.05) increased CD163 cell count (M2 macrophages) compared with tissues obtained during preoperative incision biopsies. Additionally, the CD163/CD68 ratio (an indicator of M2 polarisation) was significantly (P<0.05) higher in tumour resection specimens than in biopsies. CONCLUSIONS: This study revealed for the first time an increase in M2 polarisation in samples obtained during OSCC tumour resection surgery compared with preoperative incision biopsies. The biopsy-induced tissue trauma might explain the observed shift in macrophage polarisation towards the tumour-promoting M2 type and could lead to accelerated tumour progression.

ANCA-positive vasculitis as a secondary autoimmune disease after autologous stem cell transplantation for systemic sclerosis: a case report.

Autologous stem cell transplantation (SCT) is increasingly used to treat autoimmune diseases (AD), in particular systemic sclerosis (SSc). Secondary autoimmune diseases are a known complication after autologous stem cell transplantations for any cause. A 43-year-old man had received an autologous stem cell transplantation for an aggressive diffuse cutaneous SSc. After mobilisation with cyclophosphamide and Granulocyte-Colony-Stimulating Factor stem cells were CD34-selected. The patient received a conditioning regimen with cyclophosphamide and Antithymocyte globulin. He had an excellent response with the modified Rodnan Skin Score decreasing from 34 to 3. One year and 4 months after SCT mild erythrocyturia without acanthocytes and proteinuria were seen for the first time on routine urinalysis. During the following year erythrocyturia increased to 131 erythrocytes /µl and protein excretion to 628 mg/g creatinine. At that time, acanthocytes of 25% finally could be detected. Due to the clearly nephritic constellation in urinalysis a renal biopsy was performed, which revealed mild global and focal-segmental sclerosing and focal-segmental proliferative glomerulonephritis without any signs of a IgA-nephropathy. The result was compatible with a renal manifestation of a small-vessel vasculitis. During the following laboratory workup ANCA of a perinuclear pattern with specificity for myeloperoxidase in high titers could be detected. Therefore the diagnosis of a p-ANCA-positive glomerulonephritis was established. As treatment, the patient received Rituximab, which turned out to be effective. We provide the first report of a patient who developed a p-ANCA-associated vasculitis after autologous stem cell transplantation for an autoimmune disease, namely systemic sclerosis.

Tibetans exhibit lower hemoglobin concentration and decreased heart response to hypoxia during poikilocapnia at intermediate altitude relative to Han Chinese.

Background: High-altitude populations exhibit distinct cellular, respiratory, and cardiovascular phenotypes, some of which provide adaptive advantages to hypoxic conditions compared to populations with sea-level ancestry. Studies performed in populations with a history of high-altitude residence, such as Tibetans, support the idea that many of these phenotypes may be shaped by genomic features that have been positively selected for throughout generations. We hypothesize that such traits observed in Tibetans at high altitude also occur in Tibetans living at intermediate altitude, even in the absence of severe sustained hypoxia. Methodology: We studied individuals of high-altitude ancestry (Tibetans, n = 17 females; n = 12 males) and sea-level ancestry (Han Chinese, n = 6 females; n = 10 males), both who had been living at ∼1300 m (∼4327 ft) for at least 18 months. We measured hemoglobin concentration ([Hb]), hypoxic ventilatory response (HVR), and hypoxic heart rate response (HHRR) with end-tidal CO2 (PetCO2) held constant (isocapnia) or allowed to decrease with hypoxic hyperventilation (poikilocapnia). We also quantified the contribution of CO2 on ventilation and heart rate by calculating the differences of isocapnic versus poikilocapnic hypoxic conditions (Δ V˙I/ΔPetCO2 and ΔHR/ΔPetCO2, respectively). Results: Male Tibetans had lower [Hb] compared to Han Chinese males (p < 0.05), consistent with reports for individuals from these populations living at high altitude and sea level. Measurements of ventilation (resting ventilation, HVR, and PetCO2) were similar for both groups. Heart rate responses to hypoxia were similar in both groups during isocapnia; however, HHRR in poikilocapnia was reduced in the Tibetan group (p < 0.03), and the heart rate response to CO2 in hypoxia was lower in Tibetans relative to Han Chinese (p < 0.01). Conclusion: These results suggest that Tibetans living at intermediate altitude have blunted cardiac responses in the context of hypoxia. Hence, only some of the phenotypes observed in Tibetans living at high altitude are observed in Tibetans living at intermediate altitude. Whereas blunted cardiac responses to hypoxia is revealed at intermediate altitudes, manifestation of other physiological adaptations to high altitude may require exposure to more severe levels of hypoxia.

Transvenous Renal Transplant Biopsy via a Transfemoral Approach.

Percutaneous renal biopsy (PRB) of kidney transplants might be prevented by an elevated risk of bleeding or limited access to the allograft. In the following, we describe our initial experience with 71 transvenous renal transplant biopsies in 53 consecutive patients with unexplained reduced graft function who were considered unsuitable candidates for PRB (4.2% of all renal transplant biopsies at our institution). Biopsies were performed via the ipsilateral femoral vein with a renal biopsy set designed for transjugular renal biopsy (TJRB) of native kidneys. Positioning of the biopsy system within the transplant vein was achievable in 58 of 71 (81.7%) procedures. The specimen contained a median of 10 glomeruli (range 0-38). Tissue was considered as adequate for diagnosis in 56 of 57 (98.2%) biopsies. With respect to BANFF 50.9% of the specimen were adequate (>10 glomeruli), 47.4% marginally adequate (1-9 glomeruli) and 1.8% inadequate (no glomeruli). After implementation of real-time assessment all specimen contained glomeruli. One of the fifty-eight (1.8%) procedure-related major complications occurred (hydronephrosis requiring nephrostomy due to gross hematuria). Transfemoral renal transplant biopsy (TFRTB) is feasible and appears to be safe compared to PRB. It offers a useful new alternative for histological evaluation of graft dysfunction in selected patients with contraindications to PRB.

Acute kidney injury caused by tenofovir disoproxil fumarate and diclofenac co-administration.

OBJECTIVES: The renal elimination of tenofovir (TFV) may be subject to renal drug-drug interactions that may increase the risk of kidney injury. Case reports indicated that diclofenac might increase TFV-associated nephrotoxicity via a drug-drug interaction, leading to an increased intracellular TFV concentration in proximal tubular cells. METHODS: A retrospective analysis of data for all patients from the Frankfurt HIV Cohort (FHC) who had diclofenac prescriptions between January 2008 and June 2012 was carried out. RESULTS: Among 89 patients with diclofenac use, 61 patients (68.5%) were treated with tenofovir disoproxil fumarate (TDF) and 28 patients (31.5%) were treated with TDF-sparing combination antiretroviral therapy (cART). Thirteen patients (14.6%) developed acute kidney injury (AKI) shortly after initiating diclofenac treatment. AKI occurred exclusively in TDF-treated patients, although all had previously stable renal function. All cases were accompanied by new onset of at least two parameters indicating proximal tubular damage, such as normoglycaemic-glucosuria and hypophosphataemia. TFV-associated nephrotoxicity was demonstrated by renal biopsy in four cases. Additionally, 11.5% of patients on TDF treatment developed new-onset proximal tubular damage, while having a preserved glomerular filtration rate. In contrast, diclofenac did not affect renal function in patients with TDF-sparing cART, as only one case of isolated hypophataemia was observed in these patients. In univariate analysis, risk factors for AKI were TDF-containing cART (P = 0.0076) and pre-existing hypophosphataemia (P = 0.0086). CONCLUSIONS: Drug-drug interaction caused by diclofenac could exacerbate TFV-associated nephrotoxicity. Diclofenac should be used with caution in patients on TDF therapy, especially in those with hypophosphataemia. Our findings need to be confirmed in larger studies.

A typical Wegeners granulomatosis -- but not pauci-immune!

We present a the case of 58-year old man who was admitted to hospital with typical clinical features (bloody nasal discharge, arthralgia, acute kidney injury with a nephritic syndrome) consisting with Wegeners granulomatosis (WG). CT-scan showed pulmonary nodules and antineutrophil cytoplasmatic antibodies (ANCA) were elevated. A kidney biopsy showed a crescentic glomerulonephritis, but not pauci-immune-immune with a histopathological staining of a mesangioproliferative IgA-glomerulonephritis. The patient was put on prednisolone and i.v. cyclophosphamid (CYCLOPS-protocol (1). The anti-proteinase-3 antibody titer decreased and the CT-scan showed decreased activity of Wegener's granulomatosis (BVAS 26 dropped to 2) and the patient`s serum creatinine level was stable. The exact nosological relation of mesangial IgA-nephropathy to WG is still unclear. This case underlines that knowledge of renal histology is essential in the management of patients with renal disease, especially in patients with hematuria and/or proeinuria with positive ANCA.

[Maculo-papular exanthem with acute renal failure. Drug-induced hypersensitivity syndrome]. / Makulopapulöses Exanthem mit akuter Niereninsuffizienz. Arzneimittelinduziertes Hypersensitivitätssyndrom.

Acute renal failure caused by interstitial nephritis as part of a drug hypersensitivity syndrome constitutes a rare, but potentially life-threatening adverse drug reaction. We describe a patient with a mild maculo-papular rash accompanied by eosinophilia after prolonged treatment with meropenem, vancomycin, and moxifloxacin. Subsequently, a rapidly progressing renal failure developed which dominated the clinical picture. Upon cessation of all suspected drugs and therapy with high-dose steroids for 6 weeks, the renal function slowly returned to normal.

Sympathetic blockade prevents the decrease in cardiac VEGF expression and capillary supply in experimental renal failure.

Uremic cardiomyopathy of men and rodents is characterized by lower myocardial capillary supply that in rats could be prevented by central and peripheral blockade of the sympathetic nervous system. The underlying pathomechanisms remain largely unknown. We investigated whether alterations of cardiac vascular endothelial growth factor (VEGF) gene and protein expression were involved. In our long-term experiment, we analyzed whether VEGF gene and protein expression was altered in the heart of male Sprague-Dawley rats with either sham operation (sham, n=10) or subtotal nephrectomy (SNX, n=10). In our short-term experiment (17 sham, 24 SNX), the effect of a putative downregulation of sympathetic nervous activity by surgical renal denervation (interruption of renal afferent pathways) on cardiac gene expression of VEGF, flt-1, and flk-1 and on myocardial capillary supply was analyzed. In the long-term study, cardiac capillary supply and vascular endothelial growth factor gene and protein expression were significantly lower in SNX than in sham. In the short-term experiment, cardiac VEGF mRNA expression was significantly lower in untreated SNX (4,258±2,078 units) than in both sham groups (11,709±4,169 and 8,998±4,823 units); this decrease was significantly prevented by renal denervation (8,190±3,889, P<0.05). We conclude that cardiac VEGF gene and protein expression is reduced in experimental renal failure, and this may be considered as one potential reason for impaired myocardial adaptation under the situation of cardiac hypertrophy. The beneficial effect of sympathetic downregulation on cardiac structure and function in renal failure may be at least in part explained by increased cardiac VEGF gene expression.

The Arp2/3 complex nucleates actin filament branches from the sides of pre-existing filaments.

Regulated assembly of actin-filament networks provides the mechanical force that pushes forward the leading edge of motile eukaryotic cells and intracellular pathogenic bacteria and viruses. When activated by binding to actin filaments and to the WA domain of Wiskott-Aldrich-syndrome protein (WASP)/Scar proteins, the Arp2/3 complex nucleates new filaments that grow from their barbed ends. The Arp2/3 complex binds to the sides and pointed ends of actin filaments, localizes to distinctive 70 degrees actin-filament branches present in lamellae, and forms similar branches in vitro. These observations have given rise to the dendritic nucleation model for actin-network assembly, in which the Arp2/3 complex initiates branches on the sides of older filaments. Recently, however, an alternative mechanism for branch formation has been proposed. In the 'barbed-end nucleation' model, the Arp2/3 complex binds to the free barbed end of a filament and two filaments subsequently grow from the branch. Here we report the use of kinetic and microscopic experiments to distinguish between these models. Our results indicate that the activated Arp2/3 complex preferentially nucleates filament branches directly on the sides of pre-existing filaments.

Msx-1 is suppressed in bisphosphonate-exposed jaw bone analysis of bone turnover-related cell signalling after bisphosphonate treatment.

OBJECTIVES: Bone-destructive disease treatments include bisphosphonates and antibodies against receptor activator for nuclear factor κB ligand (aRANKL). Osteonecrosis of the jaw (ONJ) is a side-effect. Aetiopathology models failed to explain their restriction to the jaw. The osteoproliferative transcription factor Msx-1 is expressed constitutively only in mature jaw bone. Msx-1 expression might be impaired in bisphosphonate-related ONJ. This study compared the expression of Msx-1, Bone Morphogenetic Protein (BMP)-2 and RANKL, in ONJ-affected and healthy jaw bone. MATERIAL AND METHODS: An automated immunohistochemistry-based alkaline phosphatase-anti-alkaline phosphatase method was used on ONJ-affected and healthy jaw bone samples (n = 20 each): cell-number ratio (labelling index, Bonferroni adjustment). Real-time RT-PCR was performed to quantitatively compare Msx-1, BMP-2, RANKL and GAPDH mRNA levels. RESULTS: Labelling indices were significantly lower for Msx-1 (P < 0.03) and RANKL (P < 0.003) and significantly higher (P < 0.02) for BMP-2 in ONJ compared with healthy bone. Expression was sevenfold lower (P < 0.03) for Msx-1, 22-fold lower (P < 0.001) for RANKL and eightfold higher (P < 0.02) for BMP-2 in ONJ bone. CONCLUSIONS: Msx-1, RANKL suppression and BMP-2 induction were consistent with the bisphosphonate-associated osteopetrosis and impaired bone remodelling in BP- and aRANKL-induced ONJ. Msx-1 suppression suggested a possible explanation of the exclusivity of ONJ in jaw bone. Functional analyses of Msx-1- RANKL interaction during bone remodelling should be performed in the future.

[Evaluation of a renal biopsy: what information is important for nephrologists?]. / Beurteilung der Nierenbiopsie: Was der Nephrologe vom (Nephro-)Pathologen wissen will.

A kidney biopsy is an important and frequently used diagnostic tool in routine nephrology. In order to obtain relevant clinical information from a renal biopsy close cooperation between clinicians and pathologists is mandatory. The better the information obtained from nephrologists and the better the understanding by nephrologists and the quality of the kidney biopsy, the more rewarding is the information from pathologists. The following paper will discuss some practical aspects regarding the interaction between nephrology and pathology which may not be known or poorly handled and may thus cause misunderstanding. In order to facilitate interaction between clinicians and pathologists some guidelines concerning the procedure and work-up of routine kidney biopsies have been established and will be discussed in detail.

[Kidney transplant pathology]. / Nierentransplantatpathologie.

Biopsy of the transplanted kidney plays an important role in the care and treatment of patients after kidney transplantation. Today the renal biopsy is a standard procedure which is performed early after renal transplantation in the case of a primary non-functioning graft or a significant rise in serum creatinine. On the other hand, a kidney biopsy is performed if an acute or creeping rise in serum creatinine or acute onset of proteinuria or erythrocyturia is observed during follow-up. Furthermore, zero biopsies or intraoperative biopsies of the graft are important in order to obtain information about the initial quality of the graft. This is particularly important in view of the shortage of donor organs and the resulting necessity to accept increasingly marginal organs, such as for example in the ESP program. In addition, an increasing number of transplant centres perform protocol biopsies, i.e. biopsies that are not based on clinical indication, but are performed at a certain time point after transplantation to detect subclinical rejections as well as histological alterations pointing to chronic allograft damage. Additionally, there is much scientific interest in protocol biopsies.

[Calciphylaxis. A call for interdisciplinary cooperation]. / Kalziphylaxie. Eine nephrologisch-dermatologische Herausforderung.

Calciphylaxis is a rare, often very painful and potentially life-threatening disorder at the interface between nephrology and dermatology. It is characterized by skin lesions and ulcerations following calcification and occlusion of cutaneous arterioles. Most patients have chronic kidney disease or are on dialysis. A concert of various, still incompletely understood local and systemic risk factors is necessary to cause the development of calciphylaxis. Since randomized prospective trials are missing, interdisciplinary treatment is based on pathophysiological considerations as well as evidence derived from case reports or case series. Normalization of mineral metabolism, intensifying dialysis and avoidance of coumarins, as well as administration of calcimimetics, bisphosphonates and sodium thiosulfate and hyperbaric oxygen therapy are often used. Supportive measures include analgesics, antibiotics and local wound care. We have initiated an internet-based registry for patients with calciphylaxis in order to collect data for improved patient care (with support from Amgen) (www.calciphylaxie.de).

[Calciphylaxis. A less well-known, clinically relevant disease]. / Kalziphylaxie. Ein wenig bekanntes, klinisch relevantes Krankheitsbild.

Calciphylaxis is a rare disease which has been increasingly reported in recent decades and has consequently shifted into the focus of clinical and scientific research. The clinical picture is characterized by extensive ischemic ulcerations of the skin and subcutis. Histologically, the small vessels in these lesions show prominent calcifications. Due to the extensive areas of ulceration and necrosis as well as frequently present comorbidities, patients with calciphylaxis are prone to infection and sepsis. In this work, we describe the case of a female kidney-transplant patient with vasculitis who, despite good graft function, developed a fulminant calciphylaxis of both thighs 4 years post transplantation and died of septic complications. The differential diagnoses as well as clinical procedures are described in detail in the case history. In the discussion, we give an overview of the current state of knowledge regarding the etiopathogenesis, risk factors, diagnostic measures and clinical management of calciphylaxis.

[COVID-19 and kidney involvement]. / COVID-19 und Nierenbefall: Pathologie.

Apart from the pulmonary disease, acute kidney injury is one of the most frequent and most severe organ complications in severe coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could also be detected in renal tissue. Patients with chronic kidney disease and on dialysis as well as kidney transplantation patients represent a particularly vulnerable population. The increasing number of patients infected with SARS-CoV­2 has aroused increased interest in the exact pathophysiology and morphology of kidney damage as well as the direct detection of the virus in the kidneys, which in contrast to the lungs is overall more difficult to perform. Meanwhile, data from several large autopsy and kidney biopsy studies are now available. While the detection of SARS-CoV­2 RNA in tissue leads to consistently reproducible results, the use of electron microscopy for visualization of the virus is critically discussed due to various artefacts. The exact and direct effects of SARS-CoV­2 on the kidneys are not yet known in detail and are currently the focus of intensive research.