Discoidin domain receptor-1 and periostin: new players in chronic kidney disease.

The incidence and prevalence of chronic kidney disease represents an important problem for public health. In renal diseases, the main histologic alterations derive from the development of renal fibrosis which results from the loss of the balance between pro- and anti-fibrotic factors. Tyrosine kinase receptors (RTKs) and matricellular proteins (MPs) are nowadays studied as potential modulators of renal injury. RTKs regulate cell cycle, migration, metabolism and cellular differentiation. Discoidin domain receptor-1 (DDR-1) is an RTK that has been extensively studied in cancer, and lung and renal diseases. It modulates inflammatory recruitment, extracellular matrix deposition and fibrosis; in renal diseases, it appears to act independently of the underlying disease. MPs regulate cell-matrix interactions and matrix accumulation, cellular adhesion and migration, and expression of inflammatory cells. Periostin is an MP, mainly studied in bone, heart, lung and cancer. Several studies demonstrated that it mediates cell-matrix interactions, migration of inflammatory cells and development of fibrosis. Recently, it has been reported in several nephropathies. In this review, we discuss the potential pathological roles of DDR-1 and periostin focussing on the kidney in both experimental models and human diseases.

The impact of recurrence of primary glomerulonephritis on renal allograft outcome.

Twenty-yr patient and death-censored graft survival of 348 kidney transplant recipients with primary glomerulonephritis (GN) and of 696 matched controls were 82.2% in GN patients and 75% in controls (p = 0.037) and 49.5% and 54%, respectively (p = 0.013). GN patients had a higher incidence of graft failure than controls even considering death as a competing risk (p = 0.004). In the GN group, graft survival of deceased and of living donor recipients was similar. At multivariate analysis, GN as primary disease (RR: 1.47), delayed graft function recovery (RR: 2.34), acute rejection (RR: 2.36), and any PRA positivity (RR: 1.01) were predictive of graft loss. GN recurred in 85 of 348 grafts (24.4%), and 43 were lost for recurrence. In non-recurrent patients, graft survival at 20 yr was significantly better than in recurrent patients (59.4% vs. 24.4%, p = 0.000), but not different from that of controls (59.4 vs. 54%, p = 0.9). At multivariate analysis, young age at transplantation (RR: 0.97), shorter duration of dialysis (RR: 1.05 per each dialysis year), and graft from living donors (RR: 1.668) were independent predictors of recurrence. Patients with primary GN have reduced graft survival in comparison with controls, and this is mainly due to recurrence of original disease. However, the most frequent recurrence in living recipients does not compromise graft survival.

[Hypocomplementemic tubulointerstitial nephritis in IgG4-related disease]. / Nefrite tubulo-interstiziale ipocomplementemica in IgG4-related disease.

A novel lymphoproliferative disorder producing plasma cell expansion in the affected organ with fibrotic or sclerosing changes, known as ''IgG4-related disease'', was defined in Japan by Umehara's group in 2010. We present the first case reported in Italy. In 2007, a 63-year-old man presented with epigastric pain and elevated serum lipase levels. Computed tomography of the abdomen revealed a Kuttner's tumor of the pancreas. The patient underwent a biliary-enteric anastomosis, and biopsy of the pancreas revealed massive infiltration of lymphocytes and plasma cells. The patient was diagnosed with chronic sclerosing pancreatitis. After one year, he began to show signs of sicca syndrome and at the same time developed progressive renal failure. Immunological tests revealed hypocomplementemia, and the renal biopsy specimen showed diffuse interstitial inflammation. The infiltrate was composed of lymphocytes, while infiltrating plasma cells showed immunoreactivity to IgG-4. Sialography using a radioisotope revealed severe involvement of the salivary glands, and Schirmer's test gave a positive result. This led us to diagnose hypocomplementemic tubulointerstitial nephritis in IgG4-related disease. Corticosteroid treatment resulted in rapid improvement including disappearance of the sicca syndrome and progressive amelioration of renal function. After six months, we discontinued steroid administration and started mycophenolate mofetil to maintain a low degree of immunosuppression. Follow-up after two years showed that this therapy continued to be quite effective in our patient.

Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis.

BACKGROUND: Previous studies have documented the high frequency of thrombosis and fetal loss in patients with lupus nephritis and antiphospholipid (aPL) antibodies, but there is little information on the impact of aPL antibodies on the outcome of lupus nephritis. The aims of this study are to evaluate the prevalence of aPL antibodies in patients with lupus nephritis and assess their prognostic value for thrombosis and pregnancy morbidity and impact on long-term renal outcome. METHODS: One hundred eleven patients with lupus nephritis followed up for a mean of 173 +/- 100 months were tested regularly for immunoglobulin G (IgG) and IgM anticardiolipin antibodies and lupus anticoagulant. RESULTS: The overall prevalence of aPL antibodies was 26%. In follow-up, 79% of aPL antibody-positive patients experienced thrombotic events and/or fetal losses, and aPL antibodies were associated significantly with arterial or venous thrombosis (P = 0.00001), pregnancy morbidity (P = 0.045), thrombocytopenia (P = 0.0015), and persistent arterial hypertension (P = 0.028). aPL antibodies were significantly more frequent in patients with biopsy-proven membranous lupus nephritis (P = 0.01). A strong association between aPL antibodies and the development of chronic renal insufficiency in the long-term outcome also was found (P = 0.01). With multivariate analysis, aPL antibody positivity (P = 0.02), high plasma creatinine level at presentation (P = 0.01), and chronicity index (P = 0.00004) were independent predictors of chronic renal function deterioration. CONCLUSION: Detection of aPL antibodies in patients with lupus nephritis is useful not only to identify patients at risk for vascular and obstetric manifestations, but also for their potential deleterious impact on renal outcome.

The first case of IgG4-related disease in Italy.

BACKGROUND: Recently, Mikulicz's disease has been defined as an IgG-4 related disease, a systemic condition, where the hallmark pathology findings are lymphoplasmacytic infiltrates, immunoglobulin (Ig)G4-positive plasma cells, modest tissue eosinophilia, and intense fibrosis. CASE: We present a case of 63-year-old man who showed epigastralgia and elevated serum lipase levels. Computed tomography of the abdomen revealed a bulky mass of the pancreas, so he underwent bilious-digestive anastomosis, and biopsy of the pancreas revealed massive infiltration of lymphocytes and plasma cells. The patient was therefore diagnosed with sclerosing chronic pancreatitis (Kuttner's tumour). After one year, the patient began to exhibit signs of "sicca syndrome", and at the same time, he demonstrated progressive renal failure. Immunological tests showed hypocomplementemia, and the renal biopsy specimen demonstrated interstitial inflammation, in which infiltrate was composed of lymphocytes, while infiltrating plasma cells showed immunoreactivity to IgG4. Sialography revealed severe involvement of the salivary glands, and Schirmer's test resulted positive. CONCLUSIONS: Here, we report successful treatment of the first case in Italy of a patient with hypocomplementemic tubulointerstitial nephritis in IgG4-related disease.

Long-term prognosis of diffuse proliferative glomerulonephritis associated with infection in adults.

BACKGROUND: Infection-associated glomerulonephritis is rare in adults and its long-term prognosis is undefined. METHODS: We retrospectively evaluated the clinical course of 50 adults (30 men, 20 women) with infection-associated glomerulonephritis diagnosed in our department from 1979 to 1999. The mean follow-up was 90+/-78 months. Patients were subdivided into two groups: group 1 included those without underlying disease and group 2 included those with severe underlying disease. RESULTS: At presentation, the median age was 54 years, and 33 patients were hypertensive, 31 had nephritic syndrome, eight had nephrotic syndrome and 11 had non-nephrotic proteinuria. Patients in group 2 were significantly older and had a significantly higher proteinuria than patients of group 1. Of the 21 patients in group 2, nine had liver cirrhosis, four cancer, five diabetes, three bronchiectasis, one thalassaemia intermedia, one polymyositis and one had anti-phospholipid antibodies syndrome. At the last follow-up, five patients had died, 21 patients were in complete remission, ten had partial remission, ten had renal insufficiency and three were on chronic dialysis. Multivariate analysis showed that an underlying disease (P=0.04) and interstitial infiltration at biopsy (P=0.036) were predictors of incomplete recovery. A correlation analysis between the year of diagnosis and the clinical/ histological characteristics at presentation showed that age (P=0.05), atypical infections (P=0.01), underlying disease (P=0.01) and interstitial infiltration at biopsy (P=0.02) increased over time, while the number of patients with complete remission significantly decreased (P=0.001). CONCLUSIONS: Infection-associated glomerulonephritis may progress to chronic renal failure in a consistent number of adult hospitalized patients, particularly in those with an underlying disease and when associated with interstitial infiltration at biopsy.