Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy.

We investigated Toll-like receptors (TLR-3, -4 and -7) expression in circulating mononuclear cells of patients with immunoglobulin A nephropathy (IgAN), a disease with debated relationships with mucosal immunity. TLR-4 expression (detected by fluorescence activated cell sorter) and mRNA transcriptional levels (Taqman) were significantly higher in patients with IgAN than in healthy controls (P = 0.00200 and P = 0.0200). TLR-3 and TLR-7 were not modified significantly. In IgAN patients proteinuria was correlated significantly with TLR-4 expression (P = 0.0312). In a group of nephrotic syndromes, TLR-3, -4 and -7 expression was similar to healthy controls. A significant difference in TLR-4 expression and mRNA levels was found between very active IgAN patients (proteinuria > 1 g/1.73 m(2)/day in association with severe microscopic haematuria) and inactive patients (proteinuria < 0.5 g/1.73 m(2)/day, with absent or minimal haematuria). No correlation with levels of aberrantly glycosylated IgA1, age, renal biopsy features or therapy was found. This study shows for the first time an up-regulation of TLR-4 in circulating mononuclear cells of patients with IgAN, particularly in association with proteinuria and heavy microscopic haematuria.

[Non-immunological therapy in nephropathies leading to chronic renal failure and in post-transplant chronic renal dysfunction]. / La terapia non immunologica delle nefropatie con insufficienza renale cronica e della disfunzione cronica da trapianto.

With its aging population, the Western world is experiencing a significant increase in the prevalence of chronic kidney disease, which has actually been defined as ''pandemic''. The high mortality and comorbidity, especially in terms of cardiovascular disease, have led to a significant increase in hospitalizations and rising public health expenditure, setting a trend that will become unsustainable in the next decades, even in the most developed countries. These epidemiological data have underlined the need for prevention campaigns and urged researchers and clinicians to develop new and more specific treatments able to slow down the progression of chronic kidney disease towards dialysis. To obtain such results, a deeper understanding of the pathogenetic mechanisms of nephropathy progression is mandatory. Once sclerosis is established and the initial pathogenetic noxa, whether or not involving the glomeruli, has been extinguished, the sclerotic progression of different nephropathies follows a standard pathway, irrespective of the initial cause. The achievement of an effective therapy for this condition, in native kidneys as well as transplanted organs, is the third-millennium challenge for nephrologists. In this review we will first describe the main risk factors and pathogenetic mechanisms involved in nephropathy progression and then discuss the results obtained with drugs that basic research has identified as potentially useful in experimental animal models as well as rigorous clinical trials.

[Acute pyelonephritis in adults]. / La pielonefrite acuta nella popolazione adulta.

Acute pyelonephritis (APN) is a frequent and possibly severe pathological condition responsible for more than 100,000 hospitalizations per year in the United States. Etiology is prevalently Escherichia coli, and risk factors include sexual activity, genetic predisposition, old age and infection via urological instrumentation. The exact correlation between APN and vesicoureteral reflux has not yet been defined. Diagnosis of APN may be clinical, but examination using computed tomography (CT) or nuclear magnetic resonance (NMR) spectroscopy allows a more precise definition and may provide evidence of abscesses. Severe cases should be treated with a fluoroquinolone or extended-spectrum cephalosporin associated or not with aminoglycoside. Treatment should be continued for at least 10 days. Long-term evolution of APN is still unknown, even if formation of cortical scars and possible development of macroalbuminuria or renal failure are described. Pregnancy, diabetes and renal transplantation represent situations in which APN may be particularly severe. Formation of renal abscesses is underestimated and must be evaluated by CT or NMR spectroscopy evaluation. Abscesses must be drained only if they are of great size.

[Thrombotic microangiopathy during urinary tract infection]. / Un caso di microangiopatia trombotica in corso di infezione urinaria.

An 84 year-old woman was admitted because of sepsis, thrombocytopenia, anaemia and acute renal failure that required hemodialysis. The diagnostic tests performed during hospitalization showed a severe urinary tract infection due to Enterococcus faecalis, resulting in mild sepsis. This infection was responsible for acute tubular necrosis and thrombotic microangiopathy, in a clinical context of difficult differential diagnosis and hemolytic-uremic syndrome.

Single kidney function: effect of acute protein and water loading on microalbuminuria.

The hyperfiltration induced by an acute response to an oral protein and water load was investigated to ascertain whether it can modify the urinary albumin excretion (UAE) in the microalbuminuric range by further increasing the glomerular filter permeability. To this end, six patients with a single kidney selected as having microalbuminuria on a regular diet without the clinical or laboratory data of overt renal disease and eight healthy subjects received a short-term protein and water load (150 g of meat-derived protein and 1 liter of water). In patients with one kidney, mean basal UAE values were significantly higher than in control subjects (p less than 0.006), whereas endogenous creatinine clearance values were only slightly lower (p greater than 0.05). One hour after the protein and water load, an abrupt increase in microalbuminuria levels was found in patients with one kidney and mean UAE values were significantly higher than in control subjects (p less than 0.002), whereas mean creatinine clearance values were significantly lower in patients than in control subjects (p less than 0.01). High UAE (p less than 0.002) and low creatinine clearance (p less than 0.002) values were maintained over the following four hours in patients with one kidney. These data suggest that in the single kidney with reduced renal functional reserve, an oral protein and water load magnifies the pre-existing loss of glomerular permselective properties due to chronic hyperfiltration as manifested by a further increase in microalbuminuria.

In vitro study of Fc-receptor function in autoimmune diseases.

A simple test for studying in vitro Fc-receptor function of mononuclear phagocytes is described. Immune phagocytosis is analyzed as a dynamic phenomenon by using nearly pure suspensions of monocytes incubated for diverse times with autologous erythrocytes sensitized with highly purified IgG. In a series of normal volunteers and patients with vasculitis a strict correlation has been found between this in vitro assay and the measure of splenic clearance of IgG-coated red blood cells (RBC), the classical approach for studying in vivo macrophage Fc-receptor function by using sodium chromate 51Cr as tag. The use of this in vitro assay appears to be valuable mainly in cases requiring repeated measurements of Fc-receptor function for monitoring the course of disease or the effects of therapy.

Glomerulonephritis with organized deposits: a mesangiopathic, not immune complex-mediated disease? A pathologic study of two cases in the same family.

Similar glomerular changes (marked widening of the mesangial stalk, irregular basement membrane thickening, and presence of mesangial and subendothelial deposits) were observed by light microscopy in renal biopsy specimens from two patients (mother and daughter) affected by nephrotic syndrome. Electron microscopy disclosed huge glomerular electron-dense deposits containing 12-nm fibrils in both patients. Immunohistochemical investigations performed with antisera anti-immunoglobulin (Ig) and anti-complement fractions, anti-laminin, anti-collagen IV, and anti-fibronectin (FN) showed scant and focal Ig and complement deposits and strong deposits of FN in the mesangium and along glomerular basement membranes. Most glomerular FN was plasma-derived, as shown by immunohistochemical tests with monoclonal antibodies specific for both plasma and cell-derived FN (IST-4) and for cell-derived FN (IST-9). Electron-dense deposits with fibrillar component could hardly correspond to the Ig and complement deposits, whereas they could be related to FN deposits. Since it is known that in glomeruli FN binds to Ig and immune complexes, and the latter seem to be too scant to justify light and electron microscopic lesions and clinical findings, the hypothesis of a primary mesangiopathic glomerulonephritis in some way connected with abnormal plasma FN deposition within the glomeruli and subsequent non-specific immune reactant entrapment could be considered. We could be dealing with a peculiar form of fibrillary glomerulonephritis with rather indolent evolution, as shown by a slow decrease of glomerular function and the scarcely modified glomerular changes found in the second biopsy performed in the mother 8 years after the first investigation.

Verapamil versus amlodipine in proteinuric non-diabetic nephropathies treated with trandolapril (VVANNTT study): design of a prospective randomized multicenter trial.

Angiotensin converting enzyme inhibitors (ACEI) are the most effective antiproteinuric agents and should be used as first-line drugs in both diabetic and non-diabetic proteinuric nephropathies. The role of calcium channel blockers (CCB) is much more controversial. In diabetic patients verapamil and diltiazem seem more effective than dihydropyridines in reducing urinary protein excretion, and have additive effects with ACEI, but little is available on chronic treatment of non-diabetic nephropathies for non-dihydropyridine CCBs. To test whether the combination of verapamil 180 mg or amlodipine 5 mg with trandolapril 2 mg reduces urinary protein excretion more than trandolapril 2 mg alone, we planned a prospective, randomized, double-blind, multicenter trial. The secondary aims are to evaluate the effects of both treatments on the selectivity of proteinuria and check their safety. Consecutive patients aged between 18 and 70 years with non-diabetic proteinuria > or =2 g/24 h and plasma creatinine < 3 mg/dl or creatinine clearance > or = 20 ml/min are asked to participate. After a four-week run-in during which previous antihypertensive therapy is withdrawn, a single dose of trandolapril 2 mg is given once a day in open conditions for four weeks. At the end of this period patients are randomly assigned to receive once a day, in a double blind fashion, either trandolapril 2 mg and verapamil 180 mg [plus a placebo], or trandolapril 2 mg plus amlodipine 5 mg. They are monitored after one, two, five and eight months.

Mediterranean diet and primary IgA nephropathy.

Since IgA nephropathy can be experimentally induced by alimentary antigens, mechanisms of oral immunization might be supposed also in human primary IgA nephropathy (PIgAGN). IgA immune complexes (IgAIC) are thought to play a major role in PIgAGN, hence this parameter was monitored in six PIgAGN patients subjected to diets excluding gluten, meat or eggs respectively and selected as having persistent urinary activity and high IgAIC levels. On gluten-free diet IgAIC significantly decreased over 3 different periods of 10 days (Student's t-test p 1 less than 0.03, Rank-Signed test p 2 less than 0.02), 1 month (p 1 less than 0.007, p 2 less than 0.02) and 6 months (p 1 less than 0.05, p 2 less than 0.02). IgAIC significantly increased again on a gluten containing diet over 1 month (p 1 less than 0.008, p 2 less than 0.04) and 3 months (p 1 less than 0.02, p 2 less than 0.04). After 6 months on a gluten-free diet, all patients had normal IgAIC values and decreased IgA2 subclass-IgAIC, in agreement with the hypothesis of withdrawal of an antigen challenging the mucosal immune system. These data indicate a relationship between a gluten-containing diet and high levels of IgAIC in PIgAGN patients, suggesting that dietetic factors might play a role in the different geographical distribution of this nephropathy.

Microalbuminuria in single kidney patients: relationship with protein intake.

Experimental models have shown that the reduction in renal mass induces an increase in glomerular filtration rate of the remnant nephrons, leading to proteinuria and glomerular sclerosis. Since the presence of microalbuminuria - increased urinary albumin excretion (UAE) undetectable by routine assays - can be an early sign of this phenomenon, UAE in the normo- and microalbuminuric range was measured in 24 single kidney patients with negative Albustix. Nephrectomy had been performed in 22 cases 1 to 28 years before, mostly because of renal lithiasis. Patients were selected as being normotensive, normoglycemic and free of recurrent urinary infections or stones. On regular diet (mean protein intake 1.2 g/kg/day), UAE mean values were significantly higher in single kidney patients than in 20 controls both in supine position during overnight rest (clinostatism) (37.71 +/- 56.32 vs 2.56 +/- 2.27 micrograms/min, p less than 0.001) and in erect position during moderate physical effort (orthostatism) (67.31 +/- 86.12 vs 4.59 +/- 5.73 micrograms/min, p less than 0.004). Microalbuminuria was observed in 18/24 single kidney patients in clinostatism and 15/24 in orthostatism. A subgroup of 14 patients was also studied on different protein dietetic regimens. After one month on a 0.6 g/kg/day protein containing diet, UAE mean levels significantly decreased in comparison to those found on regular diet (clinostatism: 26.15 +/- 35.93 vs 49.24 +/- 70.29 micrograms/min, p less than 0.02; orthostatism: 31.73 +/- 46.97 vs 68.92 +/- 83.53 micrograms/min, p less than 0.001). One month after a 1.6 g/kg/day protein diet UAE mean values significantly increased (clinostatism 83.99 +/- 88.04 micrograms/min, p less than 0.001; orthostatism: 117.19 +/- 116.12 micrograms/min, p less than 0.001). Our data indicate that microalbuminuria, detectable in the majority of patients with a single kidney, can be modulated by different protein intakes.

Circulating Fc-receptor blocking factors in IgA nephropathies.

Twenty-one patients with primary IgA nephropathy, 7 patients with Henoch-Schönlein nephritis and 4 patients with IgA nephropathy associated to alcoholic liver cirrhosis were tested for Fc-receptor phagocyte function by measuring the clearance of radiolabelled IgG-sensitized erythrocytes in vivo and the immune phagocytosis by monocytes in vitro. Meanwhile IgG-, IgA-, IgA1-, IgA2-, containing immune complexes, the complement components C3, C4, C3d and the HLA-A, B, DR phenotype were determined. The patients with major urinary abnormalities were well discriminated from those with only minimal hematuria by a defective macrophage function (p less than 0.01) and high levels of IgA immune complexes (p less than 0.02). Since non HLA-A, B, C, DR phenotype was prevalent in patients who had defective Fc-receptor function, whereas a significant correlation was found between Fc-receptor impairment and levels of IgA immune complexes, it appears likely that circulating blocking factors, possibly related to IgA containing immune materials, may impair macrophage function in IgA nephropathies.

Circulating immune complexes containing IgA, IgG and IgM in patients with primary IgA nephropathy and with Henoch-Schoenlein nephritis. Correlation with clinical and histologic signs of activity.

A new conglutinin solid phase assay for the detection of immune complexes containing IgA (IgAIC) and other conglutinin tests for immune complexes containing IgG and IgM (IgGIC and IgMIC) were used in studies on 34 patients affected by Berger's GN (92 sera) and 12 affected by Henoch-Schoenlein GN (61 sera). Thirty-six patients were observed over follow-up periods of 2-43 months. Levels of IgAIC in both groups of patients were significantly higher than those in healthy people. The values obtained in patients with Henoch-Schoenlein GN were statistically higher than those obtained in patients with Berger's GN. Moreover, IgAIC were frequently found to be associated with IgGIC and/or IgMIC. In both groups of patients, the IgAIC levels were significantly correlated with the presence of signs of clinical and histological activity such as the magnitude of microscopic hematuria, a past history of macroscopic hematuria and the percentage of glomeruli with florid epithelial crescents.

Plasma exchange in progressive primary IgA nephropathy.

Five patients with progressive primary IgA nephropathy (PIgAGN) were treated by plasma-exchange (PE) combined with immunosuppressive drugs. Circulating IgA-containing immune complexes (IgAIC), detected by a specific conglutinin solid phase assay, were monitored. Two patients with acute nephritic syndrome and rapidly progressing course, crescent formations and high levels of IgAIC had substantial lasting clinical improvement after several PE, with a fall in IgAIC levels. Another rapidly progressive case with marked sclerotic changes and a longer history of nephritic syndrome, but with normal levels of IgAIC, did not show any clinical improvement after PE. Two patients with a PIgAGN diagnosed several years before and presenting slowly evolutive course had no substantial clinical benefit from PE treatment. IgAIC levels, very high before PE temporarily decreased, but returned to the previous values after the end of the treatment. We conclude that PE combined with immunosuppressive treatment may be of clinical benefit for cases with acute nephritic syndrome of recent onset who still have high levels of IgAIC, even when important crescent formations are present.

[Dialysis treatments outside the hospital]. / I trattamenti dialitici extra-ospedalieri.

In the early sixties a dramatic lack of hospital dialysis facilities prompted the development of home dialysis programs. The same reasons favoured in Turin, several years later, the start of a home-dialysis program and of the first European self dialysis program in an out-of-hospital setting. In the following years continuous ambulatory peritoneal dialysis was begun. In the last few years we are experiencing a new shortening of in-hospital dialysis facilities; moreover, special attention is devoted to the costs of dialysis treatment, often overlooked in the past. It is likely that self-care and home dialysis will again aid us to solve these problems, as in the past. In this paper we report on the clinical, rehabilitative and socioeconomic results of out-of-hospital dialysis treatments, and on the possible future development of home-hemodialysis and CAPD in Piedmont.

[Acute kidney failure caused by cholesterol atheroembolism]. / L'insufficienza renale acuta da ateroembolismo colesterinico.

BACKGROUND: To describe the clinical aspects of renal failure due to cholesterol atheroembolism. METHODS: An hospital based observational study on renal failure due to cholesterol atheroembolism was carried out. Twenty-two cases (19 males, mean age 68 yrs, range 53-83 yrs) were identified from January 1992 to September 1998. RESULTS: Clinical symptoms were acute or rapidly progressive renal failure with blue toe and/or skin livedo reticularis in 13/22 cases (59%) and indolent progressive renal failure in 7/22 cases (32%). In 6/22 cases (27%) an abdominal organ involvement was evident; two (9%) had retinal cholesterol emboli, two (9%) peripheral and two (9%) central nervous system impairment. In 7 patients (32%) the cholesterol atheroembolism occurred spontaneously, while in 15 (68%) it followed invasive or interventional radiology (8 cases, 36%); cardiac or vascular surgery (4 cases, 18%); thrombolytic or anticoagulant therapy (3 cases, 14%). The time interval between the procedure at risk and the onset of symptoms or signs of cholesterol atheroembolism ranged between few hours to 60 days. Eleven patients (50%) required dialysis, which was then withheld in 4 cases (36%), owing to partial functional recovery after a median time of 30 days, ranging from 10 to 690 days. Median follow-up was 2.5 months (ranging from 2 days to 68 months), and eleven patients (50%) deceased. CONCLUSIONS: Cholesterol atheroembolism is a cause of renal failure associated with high mortality rates; its prevention needs the skill of all physicians involved in the care of patients with severe atherosclerosis.

[Biopsy experience at the G. Bosco Hospital from 1996 to 1999]. / Esperienza bioptica dell'Ospedale G. Bosco dal 1996 al 1999.

BACKGROUND: Aim of this study was a retrospective analysis of the renal biopsies performed in our Division. METHODS: Since January 1, 1996 to September 30, 1999 289 biopsies were performed on native kidneys, 90 patients were older than 65. RESULTS: The most frequent nephropathy was IgA glomerulonephritis (IgAGN) (28%), followed by membranous glomerulonephritis (MGN) (11%). In patients older than 65, the most frequent was MGN (20%), followed by IgAGN (12.2%). The total complications were 84 (29.1%) (hematomas >3 cm 1%; blood transfusion: 1.4%). Complications were not related to age, blood pressure, renal function, clinical presentation, number of shots. In 217 patients, the results obtained with two different modalities were compared: manual system (needle size=15 gauge) and automatic system (18 gauge). No statistically significant differences were found as regards the number of shots for single biopsy, number of glomeruli and major complications (1.6% vs 1.3%), while minor complications were more frequent in the second group. CONCLUSIONS: In conclusion, the number of renal biopsies performed in our Division has been increasing year after year. This trend can be partially explained by our wider indications to renal biopsy in elderly population (the data related to resident population showed the greatest prevalence of biopsies in patients 70 to 79 years old). Renal biopsy actually represents a safe examination even in elderly patients. From a technical point of view, on the basis of personal experience, 18 gauge acecut automatic needles seem to be preferred to other kind of devices.

[Glomerulonephritis in the elderly]. / Le glomerulonefriti nell'anziano.

The authors present a clinical analysis of the literature data regarding aged patients affected with glomerulonephritis (GN) and of 115 GN patients aged more than 65 years, biopsied in their own Center. Complications of renal biopsy, including the subclinical ones, were found in 19.1% of old patients compared to 19.2% of younger patients (p = NS), major complications in 5 and 1.4% respectively (p = NS). The most frequent GN was membranous GN (MGN) (27.8%), followed by IgA-GN (12%) and rapidly progressive GN (RPGN), idiopathic (8.6%) or secondary to vasculitis (8.6%). Eighteen out of 32 old MGN patients treated with alternated courses of steroids and immunosuppressive drugs for 6 months were compared to 32 MGN patients aged < 65 years identically treated. Complete remission was observed in 27.7% of cases and partial remission in 38.8% (p = NS). Complications of treatment were similar in the two groups of patients (p = NS). Patients with RPGN were treated with steroids (17 patients) plus immunosuppressive drugs (15 patients) and plasma exchange (13 patients). Systemic symptoms disappeared in 13/14 patients; ANCA became negative in all the 5 patients in whom they were detected; a 50% reduction of serum creatinine was obtained in 12 patients. These patients were compared to a control group of 26 patients aged < 65 years. Amelioration of renal function was evidenced more frequently among old patients with vasculitis (p < 0.05). Complications of treatment were more frequent among old patients with idiopathic RPGN (p < 0.05), but severe in only 1 case. Our data and data from the literature support the opportunity to perform renal biopsy in aged people, because it is as safe as in the younger population and allows a rational basis for treatment of GN. Clinical responses are similar to those of younger patients. Complications of treatment seem to be more frequent in old patients, but can be limited by some technical precautions and careful clinical monitorization.

Monocyte and macrophage Fc-receptor function in systemic vasculitis with renal involvement.

The Fc-receptor function of macrophages and monocytes was studied in 10 healthy subjects and 10 patients (5 in phase of clinical activity) affected by systemic vasculitis with histological evidence of renal involvement. Macrophage function was detected by measuring the clearance in vivo of IgG-sensitized 51Cr-labelled autologous red blood cells (RBC). In vitro immune phagocytosis of monocytes was analysed as a kinetic phenomenon by incubating IgG-coated RBC with nearly pure suspensions of peripheral monocytes. All 5 patients studied in phase of clinical activity showed a defective Fc-receptor function in both the assays, as compared with normal subjects. Since a good correlation was found between the in vitro and the in vivo methods, the use of this non-invasive in vitro procedure is proposed as a substitute for the radioactive in vivo techniques in monitoring the course of the above disease.