Idiopathic granulomatous interstitial nephritis and isolated renal sarcoidosis: Two diagnoses of exclusion.

Granulomatous interstitial nephritis is a rare finding in renal biopsy caused by drugs, infections, and inflammatory or autoimmune diseases. Idiopathic cases account for 18% of granulomatous interstitial nephritis in native kidneys. Sarcoidosis and drugs are the most common causes of granulomatous interstitial nephritis in Western countries, while in India tuberculosis prevails. Few cases of renal sarcoidosis without extrarenal involvement, that is, isolated renal sarcoidosis, have been reported. The diagnostic criteria of isolated renal sarcoidosis remain, however, unclear. Extrarenal sarcoidosis and other etiologies of granulomatous interstitial nephritis, in particular drug-related, have to be excluded. Some of these patients may develop extrarenal manifestations during follow-up. Changes in calcium and vitamin D metabolism are frequently observed in renal sarcoidosis and support its diagnosis. While non-necrotizing granulomas are a feature of sarcoidosis and drug-induced granulomatous interstitial nephritis, they also prevail in tuberculosis-associated granulomatous interstitial nephritis. Granulomatous interstitial nephritis caused by sarcoidosis and drugs usually responds to steroid therapy. A poor response to steroids may indicate an infectious etiology such as tuberculosis and should lead to a review of the initial diagnosis. This article gives an overview of the various etiologies of granulomatous interstitial nephritis, their frequency and histopathological characteristics, as well as potential biomarkers associated with renal sarcoidosis.

Identification of central venous hemodialysis catheter-related infection by a semiquantitative culture method.

BACKGROUND: Central venous hemodialysis catheter-related infection is a major cause of morbidity and mortality in the hemodialysis (HD) population. Due to an impaired immune response, symptoms and signs of infection may not be obvious, and thus bacteremia is often diagnosed and treated protractedly. In contrast, induction of the acute phase response is frequently observed in HD patients even without infection. Moreover, positive catheter cultures may result from contamination, asymptomatic colonization or infection. The aim of the present study was to compare the number of colonies from HD catheter tips, with symptoms and signs of infection in HD patients. METHODS: In a 10-year, single-center study, 53 HD patients (29 men, 24 women; mean age 66 +/- 10 years) who had their dialysis catheters removed were divided into 3 groups according to the number of colonies growing after rolling the catheter tip across blood agar (group I: <15 colonies [n=22], II: 15-50 colonies [n=15], III: >50 colonies [n=16]). RESULTS: The maximum white blood cell (WBC) count did not differ significantly between patients with low- and high-density colonization (group I: 11.746 +/- 9.680 WBC/microL vs. group III: 13.479 +/- 6.252 WBC/microL, p=NS) while maximum C-reactive protein (CRP) levels were higher in patients with high-density colonization (group I: 8.6 +/- 6.8 vs. group III: 19.2 +/- 12.2 mg/dL, p<0.05). Density of bacterial colonization was associated with the maximum body temperature (group I: 37.6 degrees C +/- 1.1 degrees C vs. 38.7 degrees C +/- 0.9 degrees C, p<0.05). Moreover patients with high-density colonization showed increased bacteremia (group I: 33% vs. group III: 93%, p<0.01) as well as an increased mortality due to septicemia (group I: 9% vs. group III: 50%, p<0.01). Patients of group II exhibited intermediate values in all analyses. CONCLUSION: The semiquantitative culture technique can help to differentiate between contamination and infection of central venous HD catheters and provides important prognostic information in dialysis patients.

[Development of systemic lupus erythematosus with focal proliferative lupus nephritis during anti-TNF-alpha therapy for psoriatic arthritis]. / Entwicklung eines systemischen Lupus erythematodes mit fokaler proliferativer Lupusnephritis unter einer Anti-TNF-alpha-Therapie bei Psoriasisarthritis.

BACKGROUND: Treatment with tumor necrosis factor-(TNF-)alpha-blocking agents is used in a variety of autoimmune diseases. In anti-TNF-alpha therapy for rheumatoid arthritis, occasionally, the development of autoantibodies as well as lupus-like syndromes have been observed, rarely, glomerulonephritides are also induced. The authors first report the development of lupus erythematosus with renal involvement in a patient with psoriatic arthritis during therapy with the soluble TNF-alpha receptor etanercept. CASE REPORT: A 70-year-old patient with long-standing psoriatic arthritis developed pleuritis, pericarditis, as well as marked arthralgias during therapy with etanercept. Laboratory investigation showed markedly increased parameters of inflammation, antinuclear antibodies (ANA), a proteinuria of 3.2 g/day, mild impairment of renal function, as well as a nephritic urinary sediment. A subsequently performed renal biopsy was diagnostic for focal proliferative lupus nephritis. After withdrawal of etanercept and initiation of a cyclophosphamide pulse therapy in combination with oral steroids, parameters of inflammation and renal function rapidly normalized; pleuritis and pericarditis were not detectable anymore. CONCLUSION: Anti-TNF-alpha therapy in patients with psoriatic arthritis or other autoimmune diseases may lead to induction of systemic lupus with renal involvement.

[Chronic interstitial nephritis in an 18-year-old due to intake of a compound analgesic]. / Chronisch-interstitielle Nephritis bei einem 18-Jährigen durch Einnahme eines Mischanalgetikums.

BACKGROUND: Renal side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are acute renal failure due to an impaired perfusion caused by inhibition of prostaglandin synthesis, acute allergic interstitial nephritis as well as acute toxic tubular necrosis. Moreover, chronic renal failure may occur due to a chronic interstitial nephritis or an analgesic nephropathy that is characterized by capillary sclerosis and papillary necrosis in addition to chronic interstitial nephritis. In contrast to acute renal insufficiency that may already occur after a single NSAID dose, analgesic nephropathy is a disease caused by long-term intake of NSAID compound analgesics and predominantly affects the middle and old age. CASE REPORT: An 18-year-old patient with a 4-year history of NSAID compound analgesic intake presented to the urology department with right-sided flank pain and increased serum creatinine. An obstruction as well as nephrolithiasis were ruled out and the patient was referred to the medical department. Urinalysis showed leukocyturia, mild microhematuria as well as proteinuria of 2.2 g/day whereupon a diagnostic kidney biopsy was performed. Histology revealed a chronic nonpurulent destructive interstitial nephritis. After cessation of analgesic intake, the serum creatinine level fell to the normal range; however, a reduced creatinine clearance persisted indicating chronic renal damage. CONCLUSION: The present case is remarkable in that chronic renal damage due to intake of a compound analgesic was already observed in an 18-year-old patient. In this context, the permission of NSAID compound analgesics and their free over-the-counter sale to adolescents need to be critically questioned.

Validation of commercially available ELISAs for the detection of circulating sclerostin in hemodialysis patients.

BACKGROUND: Sclerostin is an endocrine regulator in chronic kidney disease - mineral and bone disorder (CKD-MBD). Validation of assay comparability and pre-analytical handling is mandatory for establishment of sclerostin as a biomarker. METHODS: Blood samples (serum, EDTA, heparin and citrate plasma) were obtained from 12 hemodialysis (HD) patients after the long dialysis interval. Passing-Bablok regression analysis and Bland-Altman difference plots were used to evaluate the agreement between sclerostin levels measured with two commercially available ELISAs from TECOmedical and Biomedica. RESULTS: Independent of the sample type, the agreement of the two assays was poor with a strong proportional but no systematic bias. Compared to the TECOmedical assay, the Biomedica test yielded almost 2-fold higher sclerostin values throughout all sample types. Spike recovery and linear dilution studies revealed a higher accuracy of the TECOmedical assay (97% and 96%) compared to the Biomedica assay (118% and 78%). Sclerostin levels were stable within 4 hours after sample collection, in particular when analyzed in plasma. In contrast to the Biomedica assay, the TECOmedical showed a systematic but no proportional bias between serum and plasma samples with higher values for plasma samples. Among the 3 different plasma samples no systematic error could be documented. CONCLUSION: Careful consideration of the pre-analytical handling and comparative assay validation are necessary to facilitate a more differentiated interpretation of studies reporting circulating sclerostin levels. The presence of a proportional bias demonstrates that in HD patients the two ELISAs for measuring sclerostin should not be used interchangeably. Furthermore, caution is necessary when comparing sclerostin results obtained from different blood sample types.

Extracellular actin impairs glomerular capillary repair in experimental mesangioproliferative glomerulonephritis.

Exogenous administration of actin prevents tumour growth in mice by specifically antagonizing angiogenin, a potent inducer of neovascularization. To investigate whether the angiogenin/actin system is also of importance in renal disease, we examined the effect of actin during glomerular capillary repair in anti-Thy-1.1 mesangioproliferative glomerulonephritis. Male Wistar rats were injected intravenously with actin, a control protein, i.e. albumin, or vehicle alone at 8, 16, 24, 32, 40 and 48 h after disease induction. On day 8, actin-treated rats showed significantly more microaneurysms and persistent mesangiolysis as compared to both control groups. This was associated with increased proteinuria in actin-treated rats. Moreover, actin-treated rats showed increased counts of glomerular macrophages (+40%) and polymorphonuclear leukocytes (+100%) on day 3 as well as a decrease in glomerular endothelial area on days 3 and 8. However, no difference in early glomerular endothelial as well as non-endothelial cell proliferation was noted in actin-treated rats as compared to controls. Actin treatment had no apparent influence on mesangial cell activation (i.e. de novo expression of alpha-smooth muscle actin) or glomerular accumulation of fibronectin or type IV collagen. Additional in vitro studies demonstrated that extracellular actin inhibits the angiogenin but not VEGF(165)-induced proliferation of (glomerular) endothelial cells. Moreover, actin inhibited other, yet unidentified, serum-derived angiogenic factors. In conclusion, exogenous actin impairs glomerular capillary repair in experimental mesangioproliferative glomerulonephritis possibly due to interference with angiogenic factors such as angiogenin. Our combined in vivo and in vitro observations suggest that the release of intracellular actin during mesangiolysis is an endogenous pathway by which glomerular capillary damage is augmented.

The quest for a model of type II diabetes with nephropathy: the Goto Kakizaki rat.

The Goto Kakakizaki (GK) rat is a moderately diabetic rat strain that was developed by repeated inbreeding of glucose-intolerant Wistar rats over several generations. In contrast to many other rodent models of non-insulin-dependent diabetes, GK rats do not exhibit hyperlipidemia or obesity. Hyperglycemia in the GK rat is associated with the development of age-dependent renal structural changes that are similar to those described in patients with prolonged non-insulin-dependent diabetes mellitus who have not developed overt renal disease. Hyperglycemia in the GK rat is, however, not associated with overt proteinuria or progressive nephropathy. In the present review the metabolic characteristics as well as renal and nonrenal changes observed in GK rats are described. Moreover the effects on renal function and morphology of secondary injurious stimuli, such as mesangioproliferative glomerulonephritis and hypertension, superimposed on type II diabetes in GK rats are discussed.

[Analysis of the spectrum of nephropathies over 24 years in a West German center based on native kidney biopsies]. / Analyse des Nephropathiespektrums über 24 Jahre in einem westdeutschen Zentrum anhand von Eigennierenbiopsien.

PURPOSE: The aim of the study was to analyze the occurrence of primary and secondary glomerulopathies as well as tubulointerstitial nephropathies over time and to assess potential changes in the disease spectrum. PATIENTS AND METHODS: The authors retrospectively analyzed all kidney biopsies performed in their institution between 1983 and 2006 as well as the clinical data at the time of biopsy. RESULTS: Between January 1983 and December 2006, 359 native kidney biopsies with sufficient material for histological analysis were performed (218 men, 141 women; mean age 51.8 years). A mean of nine glomeruli per biopsy were obtained. Mean serum creatinine at the time of biopsy was 3.3 mg/dl. The most common indication for biopsy was nephrotic syndrome (31%), followed by renal insufficiency (29%) and proteinuria (14%). Primary glomerulopathies were found in 51%, secondary glomerulopathies in 28%, tubulointerstitial renal diseases in 9%, and vascular renal diseases in 12%. Among the primary glomerulopathies, IgA nephropathy was the most common diagnosis (26%), followed by mesangioproliferative glomerulonephritis (17%), membranous glomerulonephritis (16%), minimal change disease (14%), focal segmental glomerulosclerosis (FSGS; 13%), rapidly progressive glomerulonephritis (RPGN; 8%), and membranoproliferative glomerulonephritis (7%). Among the secondary glomerulopathies, the heterogeneous group of autoimmune diseases (26%) and diabetic nephropathy (25%) dominated. Comparing the period from 1983 to 1994 with 1995 to 2006, a decrease in primary FSGS from 16% to 9% as well as in RPGN from 14% to 1% was noticed, while among the secondary forms, autoimmune diseases with renal involvement increased from 14% to 31%. CONCLUSION: In the own patient population changes in the spectrum of primary and secondary glomerulopathies can be observed over time. Thereby, the distribution pattern of the various glomerulonephritides largely corresponds to the distribution described for other West European countries. An increase in the incidence of primary FSGS, as observed in non-European countries, could not be demonstrated.

Differential expression of MCP-1 and its receptor CCR2 in glucose primed human mesangial cells.

BACKGROUND: Glomerular mononuclear cell infiltration is associated with the development of a diffuse glomerulosclerosis in patients with diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the recruitment and accumulation of monocytes and lymphocytes within the glomerulus. In the present study, we examined whether the ambient glucose concentration alters the expression of MCP-1 and its receptor CCR2 in primary human mesangial cells (HMC). METHODS: MCP-1 mRNA expression was assessed by Northern blot and CCR2 mRNA expression by RT-PCR analysis. MCP-1 protein production was determined by ELISA. Migration studies were performed to assess functional MCP-1 receptor expression. RESULTS: Exposure of HMC to 30 mM D-glucose led to a 30% increase in MCP-1 mRNA expression as compared to 5 mM D-glucose and osmotic controls while there was no difference in MCP-1 protein production. Simultaneously, CCR2 mRNA expression was down-regulated in HMC exposed to 30 mM D-glucose. 5 mM D-glucose primed HMC showed a dose-dependent migration towards MCP-1 that was dose-dependently inhibited by pertussis toxin, the broad-spectrum chemokine antagonist vMIP-II as well as the CCR2 receptor antagonist (1-8del)MCP-1--demonstrating functional activity of MCP-1 receptor expression in primary HMC. In accordance with the downregulatory effects of 30 mM D-glucose on CCR2 mRNA expression no migratory response towards MCP-1 was observed under these conditions. The additional proinflammatory stimulus TNFalpha increased MCP-1 protein production in 30 as compared to 5 mM D-glucose primed HMC (2,194 +/- 568 vs. 1,422 +/- 379 pg MCP-1/10(4) cells x ml in 30 vs. 5 mM D-glucose primed HMC +24 h TNFalpha 500 U/ml, p = 0.002). However, this was not associated with an increased MCP-1 mRNA transcription. The 30 mM D-glucose induced downregulation of CCR2 mRNA expression was prevented in the presence of TNFalpha. CONCLUSION: High ambient glucose does not affect mesangial MCP-1 release and decreases its CCR2 receptor expression. However, in the presence of an inflammatory stimulus these effects of high glucose are reversed and an autocrine pathway of MCP-1 develops in mesangial cells.

Glomerular oxidative and antioxidative systems in experimental mesangioproliferative glomerulonephritis.

Increased mesangial cell proliferation is a hallmark of many glomerulopathies in humans. Whereas the pathogenic role of reactive oxygen species (ROS) in the development of experimental mesangioproliferative glomerulonephritis (GN) is well established, very little is known about the mechanisms leading to increased ROS concentrations in the glomerulus. This study therefore examined glomerular ROS and the activities of oxidative and antioxidative enzymes during the early course of mesangioproliferative anti-Thy 1.1 GN. Anti-Thy 1.1 GN was induced in male Wistar rats, and glomeruli were isolated 2, 24, and 120 h after disease induction to examine ROS levels as well as oxidative and antioxidative enzyme expression in comparison to non-nephritic controls. At all time points, increased glomerular ROS levels, particularly of hydrogen peroxide and superoxide anions, were observed. Activities of NADH-dependent and NADPH-dependent oxidative enzymes were also increased during the course of GN, whereas no increased activity of xanthine oxidase, another potential source of ROS, was detectable. Despite glomerular oxidative stress, no compensatory increase of antioxidative enzyme activities occurred. On the contrary, catalase, superoxide dismutase, and glutathione peroxidase activities even decreased during the course of disease. In tubulointerstitial samples, no increase in oxidative activity was observed in the course of disease, thus confirming that detected ROS were of glomerular origin. Our data document for the first time a pronounced dysregulation of pro-oxidative and antioxidative enzymes in mesangioproliferative GN, leading to a net increase in glomerular ROS levels. Detailed knowledge of such pathways may lead to new therapeutic approaches for GN in humans.

Hypertension superimposed on type II diabetes in Goto Kakizaki rats induces progressive nephropathy.

BACKGROUND: Type II diabetes in the Goto Kakizaki (GK) rats (derived from Wistar rats) is not associated with the development of obesity, hyperlipidemia, hypertension, or pronounced renal functional changes. The aim of this study was to investigate the effect of superimposed hypertension on renal function and morphology under conditions of hyper- and normoglycemia. METHODS: The evolution of biochemical and morphologic renal changes was examined in GK and Wistar rats treated with deoxycorticosterone acetate (DOCA) salt over 24 weeks. RESULTS: Blood pressure was increased from 6 weeks on in GK and Wistar rats with no difference in blood pressure levels between both groups (week 24, 183 +/- 14 mm Hg vs. 191 +/- 13 mm Hg, P = NS, vs. 144 +/- 6 mm Hg in normal controls, P < 0.01). A progressive increase in proteinuria was observed in hypertensive GK rats from 12 weeks on (week 24, 168 +/- 62 mg/day vs. 41 +/- 30 mg/day in hypertensive Wistar rats, P = 0.002). Histologic analysis at weeks 15 and 24 showed progressive glomerulosclerosis in hypertensive GK and Wistar rats (week 24, 13 +/- 4% vs. 8 +/- 1%, P = NS) but not in nonhypertensive GK controls. This was associated with evidence of podocyte damage (de novo desmin expression) in hypertensive as compared to nonhypertensive GK rats (week 24, score 1.4 +/- 0.1 vs. 0.8 +/- 0.1, P < 0.001) while no significant increase was observed in hypertensive vs. nonhypertensive Wistar rats. Tubulointerstitial damage was increased in hypertensive GK as compared to hypertensive Wistar rats (week 24, score 1.5 +/- 0.6 vs. 0.6 +/- 0.3, P = 0.01). By immunohistochemistry, this was associated with an up-regulation of tubulointerstitial type IV collagen as well as alpha-smooth muscle actin (alpha-SMA) expression, macrophage infiltration and cell proliferation in hypertensive GK rats. CONCLUSION: Our data demonstrate that long-standing type II diabetes alone is not sufficient to induce progressive nephropathy unless secondary injurious mechanisms such as hypertension are present. The hypertensive GK rat provides a novel model to investigate the mechanisms involved in diabetic nephropathy.

Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats.

Hyperlipidemia in conjunction with uninephrectomy leads to renal injury in rats. It is unknown whether this is due to mesangial cell or podocyte injury and whether the injuries induced by hypercholesterolemia and hypertriglyceridemia share a similar pathogenesis. Therefore, renal effects of hypercholesterolemia were studied in male rats with dietary hypercholesterolemia compared with rats on a regular diet. Renal effects of hypertriglyceridemia were studied in female Nagase analbuminemic rats (NAR). Hypertriglyceridemia was reduced in NAR by ovariectomy. Both models were studied after uninephrectomy or sham operation. Dietary hypercholesterolemia had little effect on plasma triglycerides, whereas ovariectomy in the NAR had no effect on plasma cholesterol. However, an increase in intermediate density lipoprotein cholesterol was common to both models. Dietary hypercholesterolemia and uninephrectomy separately induced a similar increase in proteinuria after 13 wk, which was additive when these interventions were combined. At this stage, only a minimal increase was present in glomerular alpha-smooth muscle actin staining, a marker of mesangial cell activation, or in mesangial matrix expansion. Moreover, platelet-derived growth factor-B chain, a marker of mesangial cell proliferation, was not increased. However, podocyte injury was prominent as evidenced by podocytic de novo expression of desmin and ultrastructural changes. Glomerular macrophage counts were increased by hypercholesterolemia but not by uninephrectomy, and were not related to the level of proteinuria. Hypertriglyceridemia and uninephrectomy in female NAR induced an increase in proteinuria after 24 wk, which was also associated with an increase in podocyte desmin expression without any mesangial activation and proliferation or matrix accumulation. Hypertriglyceridemia, proteinuria, and the increase in desmin staining were largely prevented by ovariectomy. Interstitial myofibroblast activation and tubulointerstitial injury accompanied proteinuria in both models. These findings indicate that both hypercholesterolemia and hypertriglyceridemia aggravate renal injury primarily via podocyte rather than via mesangial cell damage. Such podocyte injury is accompanied by tubulointerstitial cell activation and injury.

Selective cyclooxygenase-2 inhibition impairs glomerular capillary healing in experimental glomerulonephritis.

Selective cyclooxygenase-2 (COX-2) inhibitors have anti-inflammatory activity and reduce proteinuria in experimental membranous glomerulonephritis. Antiangiogenic properties of COX-2 inhibitors were recently reported. Whether these properties are relevant to the glomerular healing process in inflammatory glomerular diseases was investigated. For evaluation of the effects of selective COX-2 inhibitors on the glomerular healing process in a rat model of mesangioproliferative glomerulonephritis (induced by anti-Thy 1.1 antibody), a selective COX-2 inhibitor (rofecoxib or celecoxib) or vehicle was administered daily from day 1 after disease induction until euthanasia on day 6. Additional nephritic rats were treated with rofecoxib or vehicle from day 1 to day 10 and were monitored until day 28. Selective COX-2 inhibition led to significant increases in mesangiolysis (up to +71%) on days 2 and 6 and in albuminuria (up to 3.1-fold) on day 6. This augmentation of glomerular capillary damage was associated with rarefaction of glomerular endothelial cells, whereas the proliferation and activation of mesangial cells were not affected. No significant effects on the glomerular influx of polymorphonuclear neutrophils or the infiltration and proliferation of monocytes/macrophages at day 2 were noted. These effects were independent of systemic hemodynamic features, because rofecoxib did not affect systolic BP on day 2 or 5. Nephritic rats treated with rofecoxib for 10 d demonstrated persistent glomerular injury at day 28, as indicated by increased albuminuria (10-fold) and mesangial type IV collagen deposition (+24%). In normal rats, 5-d administration of rofecoxib failed to induce albuminuria or morphologic renal damage. In conclusion, selective COX-2 inhibitors impair glomerular capillary repair after mesangiolysis in rats with anti-Thy 1.1 glomerulonephritis. These data suggest that selective COX-2 inhibitors should be used with caution among patients with inflammatory endocapillary glomerular disorders.