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.

Association study of IRAK-M and SIGIRR genes with SLE in a large European-descent population.

OBJECTIVE: The aim of this study was to evaluate the relevance of genetic variants of interleukin receptor-associated kinase-M (IRAK-M) (rs11465955, rs1624395, rs1152888 and rs1370128) and single immunoglobulin IL1-1R-related molecule (SIGIRR) (rs3210908) genes in systemic lupus erythematosus (SLE) in four independent European-descent populations. METHODS: Our study population consisted of a total of 2033 SLE patients and 2357 healthy controls from Spain, Germany, Italy and Argentina. The genotyping was performed using a polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. Genetic association between the genotyped markers was determined by PLINK v1.07. RESULTS: After a meta-analysis including these four populations, a trend of association between rs11465955 (P(meta) (-analysis) = 0.06), rs1370128 (P(meta) (-analysis) = 0.07) and rs1624395 (P(meta) (-analysis) = 0.06) polymorphisms was found. However, these differences did not reach statistical significance. In addition, we did not find any association between SLE and the rs1152888 IRAK-M (P(meta) (-analysis) = 0.13) and the rs3210908 SIGIRR (P(meta) (-analysis) = 0.40) polymorphisms after the meta-analysis. No evidence of association with IRAK-M haplotypes was found. CONCLUSION: These results suggest that the tested variations of IRAK-M and SIGIRR genes do not confer a relevant role in the susceptibility to SLE in European-descent populations.

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.

Tubular atrophy, interstitial fibrosis, and inflammation in type 2 diabetic db/db mice. An accelerated model of advanced diabetic nephropathy.

OBJECTIVE: Advanced diabetic nephropathy (DN) is difficult to address experimentally in mice because available models of DN lack global glomerulosclerosis and major tubulointerstitial pathology. Accelerating the development of DN in mice would be desirable for feasible experimental validation of potential targets that mediate the progression to late stage DN. METHODS: 6 week old male db/db mice underwent uninephrectomy and the development of nephropathy was compared to wild-type mice and sham-operated db/db mice. RESULTS: Uninephrectomy at young age was associated with increased albuminuria and severe glomerulosclerosis in 37% of glomeruli at 24 weeks of age as compared to sham-operated db/db mice (8%). Uninephrectomy also increased the number of glomerular macrophages in db/db mice. The uninephrectomy-related acceleration of glomerular damage was associated with significant tubulointerstitial injury as indicated by an increase in indices of tubular cell damage, tubular dilatation, and expansion of interstitial volume. Uninephrectomy markedly increased the renal mRNA expression of Mcp-1/Ccl2, Tgf-beta, and collagen I. CONCLUSION: Early uninephrectomy can accelerate the development of advanced DN in db/db mice which may be instrumental in the design of interventional studies that intend to focus on the molecular pathology of the progression to late stage DN.

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.

Cellular and Molecular Mechanisms of Autoimmunity and Lupus Nephritis.

Autoimmunity involves immune responses directed against self, which are a result of defective self/foreign distinction of the immune system, leading to proliferation of self-reactive lymphocytes, and is characterized by systemic, as well as tissue-specific, inflammation. Numerous mechanisms operate to ensure the immune tolerance to self-antigens. However, monogenetic defects or genetic variants that weaken immune tolerance render susceptibility to the loss of immune tolerance, which is further triggered by environmental factors. In this review, we discuss the phenomenon of immune tolerance, genetic and environmental factors that influence the immune tolerance, factors that induce autoimmunity such as epigenetic and transcription factors, neutrophil extracellular trap formation, extracellular vesicles, ion channels, and lipid mediators, as well as costimulatory or coinhibitory molecules that contribute to an autoimmune response. Further, we discuss the cellular and molecular mechanisms of autoimmune tissue injury and inflammation during systemic lupus erythematosus and lupus nephritis.

Gastrointestinal manifestations associated with systemic lupus erythematosus.

Gastrointestinal symptoms are often difficult to interpret in patients with systemic lupus erythematosus. Symptoms can develop either from symptomatic autoimmune tissue injury, complications of lupus-related organ dysfunction, infections, thrombembolic manifestations of anti-phospholipid antibody syndrome, medication or unrelated disorders. We describe the gastrointestinal manifestations of lupus and discuss the diagnostic approach and therapy.

[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.

Chronic effects of early started angiotensin converting enzyme inhibition and angiotensin AT1-receptor subtype blockade in rats with myocardial infarction: role of bradykinin.

OBJECTIVE: The long-term effects and mechanisms of early started angiotensin converting enzyme (ACE) inhibition post myocardial infarction (MI) are not well understood. Chronic effects of early ACE inhibition on hemodynamics, left ventricular diastolic wall stress and remodeling were, therefore, compared to that of angiotensin AT1-receptor subtype blockade in rats with experimental myocardial infarction. The contribution of bradykinin potentiation to both ACE inhibitor and angiotensin AT1-receptor subtype blockade was assessed by cotreatment of rats with a bradykinin B2-receptor antagonist. METHODS: MI was produced by coronary artery ligation in adult male Wistar rats. The ACE inhibitor, quinapril (6 mg/kg per day), or the angiotensin AT1-receptor subtype blocker, losartan (10 mg/kg per day), administered by gavage, and the bradykinin B2-receptor antagonist, Hoe-140 (500 micrograms/kg per day s.c.), administered either alone or in combination with quinapril or losartan, were started 30 min after MI and continued for eight weeks. RESULTS: Quinapril and losartan reduced left ventricular end-diastolic pressure and global left ventricular diastolic wall stress only in rats with large MI. Pressure volume curves showed a rightward shift in proportion to MI size that was not prevented by quinapril or losartan treatment. Only the ACE inhibitor reduced left ventricular weight and this effect was prevented by cotreatment with the bradykinin antagonist. Baseline and peak cardiac index and stroke volume index, as determined using an electromagnetic flowmeter before and after an acute intravenous volume load, were restored by quinapril, whereas losartan had no effects. CONCLUSION: Treatments starting 30 min after coronary artery ligation, with either quinapril or losartan, reduced preload only in rats with large MI. Despite this unloading of the heart, structural dilatation was not prevented by this early treatment. Only quinapril improved cardiac performance and reduced left ventricular weight and this effect was abolished by cotreatment with Hoe-140, suggesting an angiotensin II blockade-independent, but bradykinin potentiation-dependent, mechanism.

Adipsic hypernatremia in two patients with AIDS and cytomegalovirus encephalitis.

In patients with acquired immune deficiency syndrome (AIDS), hypoosmolality is frequently observed, whereas hypernatremia is distinctly rare. We report two patients with advanced AIDS and cytomegalovirus (CMV) encephalitis, who developed severe hypernatremia without any thirst sensation, that is, adipsic hypernatremia. Both developed severe hypernatremia of up to 164 and 162 mmol/L, with serum osmolalities of 358 and 344 mOsmol/kg while remaining alert and denying thirst. Serum antidiuretic hormone (ADH) levels were 0.9 and 1.5 pg/mL, inappropriately low for the concomitant serum osmolalities. Vital signs were stable. During hypernatremia, urine osmolalities were 327 and 340 mOsmol/kg, and urine Na+ levels were 56 and 119 mmol/L, respectively. Periventricular white matter lesions were seen on cerebral nuclear magnetic resonance imaging (NMRI) in case 1, but the pituitary appeared normal in both cases. Survival after onset of hypernatremia was 6 and 4 weeks, respectively. Autopsy in case 1 showed typical findings of CMV encephalitis but normal pituitary, confirming that infection with HIV or CMV most likely caused the dysfunction of the central osmostat.

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.

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.

Ganciclovir and foscarnet efficacy in AIDS-related CMV polyradiculopathy.

Cytomegalovirus (CMV) polyradiculopathy is a rare complication of AIDS in which ascending motor weakness, sensory loss and urinary retention are associated with polymorphonuclear pleocytosis and positive CMV polymerase chain reaction in the cerebrospinal fluid (CSF). We describe three patients with this syndrome. One patient's paresis improved after ganciclovir therapy. Another patient deteriorated despite foscarnet treatment, but improved after ganciclovir was added. The third patient died from ascending paralysis despite ganciclovir-foscarnet combination. Reviewing the literature, we conclude that antiviral treatment reduced mortality from 100 to 22%. In patients with ascending paralysis treatment, failure may be caused by viral drug resistance, at least in some patients. Risk factors for treatment failure are preceding monotherapy for other CMV diseases or persistent CSF pleocytosis on serial CSF analysis. We suggest that these patients should therefore be treated with the alternative drug or a ganciclovir-foscarnet combination therapy.

Neurological manifestations of cytomegalovirus infection in the acquired immunodeficiency syndrome.

Cytomegalovirus (CMV) infection is one of the most important opportunistic infections in AIDS. The most common manifestation of neurological CMV disease in HIV infection is retinitis followed by encephalitis, polyradiculopathy, and multifocal neuropathy. Untreated necrotizing retinitis proceeds to blindness but can readily be diagnosed by ophthalmological examination. CMV polyradiculopathy presents as subacute leg weakness, paraesthesia, and urinary retention. Untreated patients develop ascending paralysis and die within weeks. Multifocal neuropathy commonly affects the radial, ulnar, and peroneal nerves but cranial nerves may also be involved. Confusion, cranial nerve palsies, and hyperreflexia are signs of ventriculoencephalitis, whereas the presentation of diffuse micronodular encephalitis is often asymptomatic. The diagnostic approach relies on the detection of CMV DNA in the cerebrospinal fluid for polyradiculopathy, encephalitis, and neuropathy. Neuroimaging can exclude other causes of encephalitis and polyradiculopathy. Ganciclovir, foscarnet, and cidofovir monotherapy are current medical treatment options. Intraocular administration can be used for refractory retinitis, but additional systemic prophylaxis is required to suppress extraocular disease. Ganciclovir and foscarnet have improved the prognosis of multifocal neuropathy and polyradiculopathy, but response rates for encephalitis are low. However, despite therapy survival of central nervous CMV disease is still limited to months. Recently highly active antiretroviral therapy (HAART) has decreased the overall incidence of CMV disease in AIDS. Furthermore (HAART) has become a mainstay for CMV therapy by improving the patient's immunocompetence against CMV.

Prediction of creatinine clearance from serum creatinine in patients with rheumatoid arthritis: comparison of six formulae and one nomogram.

The estimation of glomerular filtration rate is important for the medical treatment of patients with rheumatoid arthritis (RA). However, the determination of endogenous creatinine clearance (Clcr) from a 24-h urine collection is an unreliable and time-consuming procedure. We therefore tested the accuracy of six equations and one nomogram for the prediction of Clcr from serum creatinine (Scr) in 38 patients with RA and 20 controls. A positive correlation was found for all methods in the controls (r = 0.83-0.94) and RA patients (r = 0.51-0.69). The methods did not overestimate Clcr in RA. In the RA group the simple formula published by Cockcroft [Clcr = ((140 - age) x body weight)/(72 x Scr), x 0.85 for females] showed the best correlation with the measured Clcr. In RA the Cockroft formula can reliably be used to predict Clcr from Scr.

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.

Bisoprolol treatment for cyanotic spells--a 69-year-old female with uncorrected pentalogy of Fallot.

Pentalogy of Fallot is a rare cyanotic congenital heart disease characterized by biventricular origin of the aorta above a large ventricular septal defect, obstruction of the pulmonary outflow, right ventricular hypertrophy (tetralogy of Fallot), and an atrial septal defect. Mortality due to syncope, arrhythmia or congestive heart failure is about 75% by the age of 10 years and 97% by the age of 40. We report a 69-year old female with uncorrected pentalogy of Fallot who suffered from recurrent syncope during classic cyanotic spells. Treatment with bisoprolol is recommended in symptomatic children and also improved symptoms in our patient. We conclude that single patients with pentalogy of Fallot reach the seventh decade and that cyanotic congenital heart disease is a rare cause of syncope in the elderly.

Mild rhabdomyolysis after high-dose trimethoprim-sulfamethoxazole in a patient with HIV infection.

Adverse drug reactions to trimethoprim-sulfamethoxazole (TMP/SMX) are common in HIV-positive patients. However, only one case of TMP/SMX-related rhabdomyolysis has been reported, so far. We report a 55-year old-man with asymptomatic rhabdomyolysis after oral high-dose TMP/SMX for suspected PCP. Laboratory changes settled after discontinuation of the drug.

Podocyte mitosis - a catastrophe.

Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.