Refractory lupus nephritis: a survey.

'Refractory lupus nephritis' is a frequently used term but poorly defined. We conducted a survey among nephrologists and rheumatologists to spot the diversity of perceptions of this term and to better understand the clinical practice related to 'refractory lupus nephritis'. A total of 145 questionnaires completed by lupus nephritis experts were available for analysis, of which 52% were nephrologists, 34% rheumatologists, and 13% internists. Response to induction treatment was mostly assessed after six months (58%), but assessment at three months was more common with the use of the EURO lupus protocol than with other treatment protocols. Rheumatologists used urinary sediment to assess response more frequently than nephrologists (66 vs. 48%, p < 0.05, Chi2), while nephrologists conversely relied significantly more on clinical symptoms (61 vs. 31%, p < 0.0001, Chi2). Non-nephrologists quantified proteinuria preferentially by 24 h urine sampling, while the majority of nephrologists relied on the urinary protein/creatinine ratio (UPCR) or the albumin/creatinine ratio of spot urine samples (59 vs. 38%, p < 0.05, Chi2). A total of 91% were concerned about persistent immunological systemic lupus erythematosus activity. There was less concern about drug adherence, renal scarring, genetic factors or other kidney diseases. Less than 20% check for drug adherence by regularly monitoring drug plasma levels. Nephrologists considered a re-biopsy more often than rheumatologists (58 vs. 38%, p < 0.05, Chi2). Together, among lupus nephritis experts there is considerable diversity in the perception of what the term 'refractory lupus nephritis' describes and how it is defined. A consensus definition of 'refractory lupus nephritis' is needed.

Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: Chemokine (C-X-C motif) ligand 12 (CXCL12) (also known as stromal cell-derived factor-1 [SDF-1]-alpha) is a homeostatic chemokine with multiple roles in cell homing, tumour metastasis, angiogenesis and tissue regeneration after acute injuries. However, its role in chronic diseases remains poorly defined, e.g. in chronic glomerular diseases like diabetic glomerulosclerosis. We hypothesised that CXCL12 may have a functional role during the evolution of diabetic glomerulosclerosis, either by assisting glomerular repair or by supporting the maladaptive tissue remodelling in response to hyperglycaemia and glomerular hyperfiltration. METHODS: To define the functional role of CXCL12 in the progression of glomerular disease, we used the CXCL12-specific inhibitor NOX-A12, an L: -enantiomeric RNA oligonucleotide (Spiegelmer). A mouse model of type 2 diabetes (db/db mice) was used. Male db/db mice, uni-nephrectomised at 6 weeks of age, received subcutaneous injections with a PEGylated form of NOX-A12, non-functional control Spiegelmer or vehicle on alternate days from 4 to 6 months of age. RESULTS: Immunostaining localised renal CXCL12 production to glomerular podocytes in db/db mice with early or advanced diabetic nephropathy. CXCL12 inhibition significantly reduced the degree of glomerulosclerosis, increased the number of podocytes, prevented the onset of albuminuria and maintained the peritubular vasculature without affecting blood glucose levels, body weight or glomerular macrophage infiltration. CONCLUSIONS/INTERPRETATION: We conclude that podocytes produce CXCL12, which contributes to proteinuria and glomerulosclerosis in our mouse model of type 2 diabetes. This novel pathomechanism provides the first evidence that CXCL12 could be a therapeutic target in (diabetic) glomerulosclerosis.

[A 68-year-old patient with atrial flutter/fibrillation, inadequate anticoagulation, subacute amaurosis, normal ESR, and lymphadenopathy]. / 68-jähriger Patient mit Vorhofflattern/Vorhofflimmern, inadäquater Antikoagulation, subakuter Amaurosis, normaler BSG und Lymphadenopathie.

We present a rare manifestation of chronic lymphatic leukemia with progressive bilateral visual loss and the typical fundoscopic picture of anterior ischemic optic nerve neuropathy (AION). Clinical symptoms were due to meningeal metastases and tumor cell infiltration of the optic nerve. The diagnostic clue was provided by lumbar puncture with pressure measurement, which made it possible to differentiate AION from papillitis and papilledema. In this case the patient was able to regain his initial visual activity after intrathecal and systemic polychemotherapy.

[CCL2/MCP1: a novel target in systemic lupus erythematosus and lupus nephritis]. / CCL2/MCP-1 als neues Target beim systemischen Lupus erythematodes und der Lupusnephritis.

Cytokine blockade, a valid therapeutic concept, is not established in lupus nephritis as yet. In lupus nephritis CCL2/MCP-1 and its chemokine receptor CCR2 are of interest because CCL2/CCR2 mediate the recruitment of macrophages and T cells in the nephritic kidney. Lupus nephritis is markedly attenuated in CCL2- or CCR2-deficient autoimmune mice. Epidemiological studies addressing mutations in the CCL2 gene support the hypothesis that CCL2 mediates renal inflammation. Meanwhile experimental studies have shown that several classes of CCL2 antagonists can control established lupus nephritis. Interestingly, therapeutic CCL2 blockade does not affect the autoimmune lymphoproliferative syndrome and the production of lupus autoantibodies. This article briefly summarizes the potential role of therapeutic CCL2 blockade in lupus nephritis.

Different roles of TiR8/Sigirr on toll-like receptor signaling in intrarenal antigen-presenting cells and tubular epithelial cells.

Toll-like receptors (TLRs) exist on both myeloid and intrinsic renal cells contributing to the initiation of innate immunity during renal infection with uropathogenic Escherichia coli. Toll-interleukin 1 receptor (IL-1R) (TIR)8/SIGIRR is an orphan receptor of the TLR/IL-1R family, which suppresses TLR signaling of immune cells and is highly expressed in the kidney. Lack of TIR8/SIGIRR is associated with enhanced renal chemokine signaling upon exposure to lipopolysaccharide (LPS). This was because of TIR8/SIGIRR expression on resident intrarenal myeloid cells rather than tubular epithelial cells which express it on basolateral and luminal membranes. The lack of TIR8/SIGIRR does not enhance TLR/IL-1R signaling in tubular epithelial cells as was observed in monocytes. TIR8/SIGIRR is induced in monocytes treated with LPS or tumor necrosis factor and interferon-gamma in a dose-dependent manner but was downregulated in treated tubule epithelial cells. This cell type-specific regulation and function did not relate to mRNA splice variants but was associated with N- and O-glycosylation of the receptor in renal cells of myeloid and nonmyeloid origin. Our studies show that resident myeloid cells contribute to TLR-mediated antimicrobial immunity in the kidney and that this function is controlled by Tir8/sigirr. TIR8/SIGIRR does not suppress TLR signaling in tubular epithelial cells, which supports their role as sensors of microbial infection in the kidney.

Lupus nephritis.

Lupus nephritis is a common complication of systemic lupus erythematosus (SLE). Early recognition of lupus nephritis requires routine serum creatinine determination, urinalysis and urinary microscopy. Since mild urinary abnormalities such as leucocyturia or proteinuria can be associated with severe lupus nephritis, a renal biopsy is usually indicated in patients with SLE and urinary abnormalities. A renal biopsy is required to determine the class of lupus nephritis which is based on histopathological criteria which have recently been revised. Aggressive immunosuppressive therapy is indicated in diffuse proliferative lupus nephritis. In class III or class V the treatment indication depends on additional prognostic criteria. Intravenous cyclophosphamide is still used but doses and intervals have been modified based on large clinical trials. Mycopheno-late may establish as an alternative for cyclophosphamide in the induction phase, but the data of the transcontinental multicenter Aspreva Lupus Management Study (ALMS) trial have not yet been published in detail. Controlled clinical trials support the use of azathioprine and mycophenolate for maintaining remission of lupus nephritis, and cyclophosphamide is no longer used in that phase. Additional control of cardiovascular risk factors and combined angiotensin and angiotensin receptor blockade are mandatory for all proteinuric SLE patients. Novel treatment options are ahead of us based on the molecular mechanisms of SLE and lupus nephritis, but as evidence from controlled clincial trials is still lacking they are not yet approved for broad clinical use. However, the treatment options for severe lupus nephritis have been improved and are likely to further improve in the near future.

[Chronic renal failure]. / Neue Konzepte bei der chronischen Niereninsuffizienz.

The elevated cardiovascular mortality seen in patients with renal insufficiency makes it imperative that this condition be detected and treated in good time. The results of recent studies have led to fundamental changes in the therapeutic approach to the patient with kidney disease. A range of new medications is now available for the treatment of complications of renal failure.

Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice.

Multipotent mesenchymal stem or stromal cells (MSC) have shown to improve outcome of acute renal injury models, but whether MSC can delay renal failure in chronic kidney disease is not known. We injected primary MSC or saline into mice that lack the alpha3-chain of type IV collagen (COL4A3), a model of chronic kidney disease with close similarities to human Alport disease. Weekly injections of MSC from week 6 to 10 of life prevented the loss of peritubular capillaries and reduced markers of renal fibrosis, that is, interstitial volume, numbers of smooth muscle actin-positive interstitial cells, and interstitial collagen deposits as compared to saline-injected COL4A3-deficient mice. However, renal function, that is, blood urea nitrogen, creatinine levels, proteinuria as well as survival of COL4A3-deficient mice were not affected by MSC injections. Although MSC were found to localize to kidneys of COL4A3-deficient mice after injection, differentiation into renal cells was not detected. However, MSC expressed growth factors, that is, vascular endothelial growth factor (VEGF) and bone morphogenetic protein-7 under basal culture conditions. In fact, VEGF mRNA levels were increased in kidneys of MSC-injected COL4A3-deficient mice and MSC supernatants enhance endothelial cell proliferation in vitro. Thus, weekly injections with MSC prevent loss of peritubular capillaries possibly owing to local production of growth factors rather than by differentiation into renal cells. The maintenance of interstitial vasculature is associated with less interstitial fibrosis but, is insufficient to delay renal failure and survival of COL4A3-deficient mice.

[Psoriatic onycho-pachydermo- periostitis]. / Psoriatische Onycho-Pachydermo-Periostitis.

BACKGROUND: Psoriatic onycho-pachydermo-periostitis is a rare manifestation of psoriatic arthritis. It is characterized by the trias of psoriatic onychosis, tender soft tissue thickening, and osteoperiostitis of the distal phalanges in the absence of distal interphalangeal arthritis. Recommendations for the treatment of symptomatic POPP are not available. AIM OF THE STUDY: Treatment of a symptomatic 49-year old male. METHODS: Sulfasalazine 1000mg b.i.d., p.o. for 8 months followed by radiotherapy of both hands with 6x0.5 Gy. RESULTS: No clinical response was observed with either of the two treatments. CONCLUSIONS: The course of this single case does not support sulfasalazine treatment or radiotherapy in psoriatic onycho-pachydermo-periostitis.

Avascular areas on nailfold capillary microscopy of patients with Wegener's granulomatosis.

Over the past 25 years, nailfold capillary microscopy (NCM) has gained diagnostic value in the field of rheumatology based on descriptive data from patients with distinct connective tissue diseases (CTD). We prospectively analysed NCM findings from 116 patients selected for NCM by one of the following indications: (1) suspected diffuse or limited scleroderma or dermatomyositis, (2) evaluation of Raynaud's phenomenon (RP) or (3) suspected small-vessel vasculitis. Nailfold haemorrhages, and enlarged and tortuous nailfold capillaries ('lupus pattern') were found to comparable degrees in patients with CTD and primary RP. Only giant loops, bushy capillaries and avascular areas indicated CTD; 92% of patients with Wegener's granulomatosis (WG) had avascular areas. From all nailfold capillary abnormalities, only bushy capillaries, giant loops and avascular areas support a suspected CTD. A lupus-like pattern is not diagnostic. Avascular areas are a typical abnormality in patients with WG, for which NCM findings have not been described previously.

Leptin serum levels are not correlated with disease activity in patients with rheumatoid arthritis.

Leptin, the ob gene product, has been proposed as a mediator of inflammatory cytokine-dependent decreased food intake and cachexia in rodents. In humans, leptin serum levels increase after administration of tumor necrosis factor-alpha (TNF-alpha) or interleukin-2 or during septicemia. However, the effect of human chronic inflammatory disease on serum leptin is unknown. We therefore determined the serum leptin level (radioimmunoassay), body mass index (BMI), percent body fat ([%BF] bioelectrical impedance analysis), and disease activity (Disease Activity Score [DAS]) in 58 patients with rheumatoid arthritis (RA) and 16 controls. The BMI, %BF, serum leptin, and ratio of leptin to %BF (leptin/%BF) did not differ significantly in 25 patients with moderate RA activity (DAS, 3.6 +/- 0.5), 33 patients with low RA activity (DAS, 1.8 +/- 0.5), and controls. A positive correlation for serum leptin and %BF was detected in all groups. Our data indicate that in RA, a human chronic cytokine-mediated inflammatory disease, the serum leptin level is directly related to %BF but not to disease activity.

MPO-ANCA-Positive crescentic glomerulonephritis: a distinct entity of scleroderma renal disease?

Scleroderma renal crisis is characterized by intimal thickening of the afferent glomerular arterioles resulting in hypertension and fibrinoid necrosis of the capillary tuff. We report a 67-year-old man with long-standing systemic sclerosis who developed normotensive progressive renal failure, proteinuria, and a nephritic urinary sediment with serum myeloperoxidase-antineutrophil cytoplasmatic antibodies (MPO-ANCA). Renal biopsy showed pauci-immune crescentic glomerulonephritis but none of the typical vascular changes of scleroderma renal crisis. Because comparable cases have recently been reported from Japan, normotensive MPO-ANCA-positive crescentic glomerulonephritis may form an entity of progressive renal failure in scleroderma.

Compression syndromes caused by substernal goitres.

Enlargement of the thyroid is common, especially in areas of endemic iodine deficiency. Substernal enlargement of a goitre can cause compression of several mediastinal structures. As a consequence of tracheal compression and tracheomalacia, syndromes of chronic respiratory distress occur and intercurrent upper respiratory infections may lead to acute respiratory failure. Superior vena cava syndrome secondary to compression by a substernal goitre may be complicated by venous thrombosis. Although dysphagia is the most frequent oesophageal symptom of a substernal goitre, upper gastrointestinal bleeding from 'downhill' oesophageal varices may be an initial presentation. Arterial compression or thyrocervical steal syndrome by large substernal goitres occasionally cause cerebral hypoperfusion and stroke. Recurrent and phrenic nerve palsies, as well as Horner's syndrome, occur secondary to non-malignant mediastinal goitres and may resolve after surgery. Substernal goitres rarely cause therapy-resistant pleural effusions, chylothorax and pericardial effusion. In conclusion, although cervical goitres are easily recognised, the initial presentation of mainly substernal goitres may be unusual.