Human Leukocyte Antigen Compatibility and De Novo Donor-Specific Antibodies in Long-term Renal Transplant Patients With Stable Graft Function.

PURPOSE: De novo donor-specific antibodies (DSA) are associated with antibody-mediated rejection leading to late renal transplant failure. The aim of this study was to evaluate whether HLA compatibility is associated with sensitization along with other risk factors. METHODS: Eighty-nine stable renal transplant recipients (47 men) were studied. Patients were classified into 2 groups according to HLA compatibility between donor and recipient, group A (1-4/8 matches) and group B (5-8/8 matches). Cold ischemia time (CIT) and delayed graft function (DGF) were recorded along with time with a functional graft. Anti-HLA antibodies were detected using a Luminex single-antigen bead assay and were further classified into DSA and non-DSA. RESULTS: HLA group A consisted of 49 (56%) transplant recipients while 38 (44%) were classified to group B, with functional grafts for 10.9 ± 6.7 and 14.8 ± 8.5 years, respectively (P = .019). Group A patients had more anti-HLA antibodies than group Β (P = .001) and this correlation was retained for DSA patients. De novo anti-HLA were detected in 40 patients; DSA were detected in 19 (21.8%). DSA (+) patients had recorded with functional renal grafts for 11 ± 5 years, compared to 14.4 ± 8.6 years (P = .048) for anti-HLA negative patients. Increased CIT and DGF were associated with anti-HLA antibodies detection but no with DSA. CONCLUSION: HLA compatibility is probably correlated with DSA in a context of a more general anti-HLA sensitization, and both have a negative effect on long-term renal graft outcome.

Th1, Th2 and Treg/T17 cytokines in two types of proliferative glomerulonephritis.

IgA nephropathy (IgAN) and focal segmental necrotizing glomerulonephritis (FSNGN) are characterized by proliferation of native glomerular cells and infiltration by inflammatory cells. Several cytokines act as mediators of kidney damage in both diseases. The aim of the present study was to investigate the role of Th1, Th2 and Treg/T17 cytokines in these types of proliferative glomerulonephritis. Simultaneous measurement of Th1 interleukin (IL-2, IL-12, tumor necrosis factor-alpha [TNF-α], interferon-gamma [INF-γ]), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), Treg/T17 transforming growth factor-beta 1 (TGF-ß1, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17) cytokines and C-C chemokines Monocyte chemoattractant protein-1 (MCP-1, macrophage inflammatory protein-1 [MIP-1] ß) was performed in first-morning urine samples, at the day of renal biopsy, using a multiplex cytokine assay. Cytokine concentrations were correlated with histological findings and renal function outcome. Urinary excretion of Th1, Th2 and Treg/Th17 cytokines were significantly higher in FSNGN compared to IgAN patients. In IgAN patients (n = 50, M/F: 36/14, M age: 40.7 [17-67] years), Th1, Th2 and T17 cytokines correlated significantly with the presence of endocapillary proliferation, while in FSNGN patients (n = 40, M/F: 24/16, M age: 56.5 [25-80] years), MCP-1 and TGF-ß1 had a positive correlation with severe extracapillary proliferation (P = 0.001 and P = 0.002, respectively). Urinary IL-17 was the only independent parameter associated with endocapillary proliferation in IgAN and with MCP-1 urinary excretion in FSNGN. Response to treatment was mainly predicted by IL-6 in IgAN, and by Th2 (IL-4, IL-6), Treg (GM-CSF) cytokines and MIP-1 ß in FSNGN. Th1, Th2 and T17 cytokines were directly implicated in renal pathology in IgAN and possibly through MCP-1 production in FSNGN. IL-17 and IL-6 seem to have a central role in inflammation and progression of kidney injury.

Immunosuppressive therapy and clinical evolution in forty-nine patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis.

Immunosuppressive therapy and clinical evolution were studied in 49 patients (29 females) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The mean age of patients at presentation was 55 years, and the mean (+/-SD) follow-up was 43 months (+/-33) (range, 3-140). Among the 49 patients, 10 had biopsy-proven Wegener's granulomatosis, 33 microscopic polyangiitis, 2 Churg-Strauss syndrome, and 4 idiopathic crescentic glomerulonephritis. IgG ANCA autoantibodies were detected in all patients. Induction therapy included pulses and oral administration of methylprednisolone (MP) with oral administration of cyclophosphamide (CP) and plasma exchange in patients with alveolar hemorrhage and serum creatinine (SCr) levels >/= 6 mg/dL. CP was converted to azathioprine (AZA) or mycophenolate mofetil (MMF) after 3-6 months of therapy. Low doses of MP with or without AZA or MMF were administered until the end of follow-up. Therapy institution resulted in remission of disease in all patients. The mean SCr levels decreased from 4.9 mg/dL (+/-2.5) at the onset of the disease to 2.8 mg/dL (+/-1.7) (P > 0.0001), and 3.2 mg/dL (+/-2.3) (P > 0.0001) after 3 and 6 months, respectively. At the end of follow-up, 17 (35%) patients progressed to end-stage renal disease after 34 months (+/-29) (range, 3-98), and 30 (61%) patients maintained sufficient renal function. Two patient deaths were attributed to immunosuppression. Patients with high SCr levels at diagnosis and severe interstitial fibrosis found in renal biopsy had poor renal outcome (P > 0.01 and P > 0.02, respectively). Induction therapy with MP and CP seems to be the regimen of choice in patients with ANCA-associated glomerulonephritis. Early diagnosis and therapy institution as well as long-term treatment lead to acceptable renal survival.

TNF-α and microalbuminuria in patients with type 2 diabetes mellitus.

AIM: Recent evidence suggests that chronic subclinical inflammation plays a key role in the pathogenesis and progression of diabetic nephropathy. Aim of the present study was to investigate possible correlation between the presence and degree of microalbuminuria and markers of inflammation in patients with type 2 diabetes mellitus (DM). PATIENTS-METHODS: Eighty patients were enrolled and clinical and laboratory data were recorded. Albumin-creatinine ratio (ACR) was calculated in first-morning urine samples. Serum and urinary tumor necrosis factor-α (TNF-α) levels were determined by ELISA. RESULTS: Forty-five patients had normoalbuminuria, 33 microalbuminuria, and 2 macroalbuminuria. Patients with microalbuminuria were older, with higher glycosylated hemoglobin levels (HbA1c) and they more frequently had diabetic retinopathy, neuropathy, and cardiovascular disease and were on treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). ACR was significantly correlated with the presence of cardiovascular disease, hypertension, and HbA1c levels and the administration of clopidogrel and ACEi or ARBs. ACR was not correlated with C-reactive protein, fibrinogen, or serum TNF-α levels but had a strong correlation with urinary TNF-α levels. CONCLUSIONS: In patients with type 2 DM, urinary, but not serum, TNF-α levels are associated with the presence and severity of microalbuminuria.

Nomogram for determining lower limit of the sural response.

OBJECTIVE: Age and height influence on sural sensory nerve action potential (SNAP) have been studied separately. Our aim was to develop an equation for predicting the lower normal limits as a function of both these factors. METHODS: One hundred fifty-eight healthy volunteers, 63 male, with mean age 45.8 and mean height 167.3 without symptoms or signs of peripheral neuropathy participated in the study. The sural SNAP was recorded at the level of the ankle joint, just posterior to the lateral malleolus, using surface electrodes. Antidromic supramaximal stimulation was performed 13 cm proximally at the posterior midcalf. RESULTS: The mean sural SNAP amplitude was 19.9+/-6.89 microV. Pearson linear correlation showed a negative correlation of the SNAP amplitude with age (R=-0.22, p=0.005) and height (R=-0.19, p=0.03). The multiple linear regression model was applied for both parameters of age and height with SNAP amplitude as the dependent parameter, producing the following equation: SNAP amplitude=62.45-0.1447 x Age-0.2147 x Height. CONCLUSIONS: Using our normal data, the computed lower limits of the 95% prediction interval for the sural SNAP amplitude of an individual subject, depending on his age and height, were calculated. SIGNIFICANCE: The individualized normal values provided by our equation are essential for the correct interpretation of sural nerve studies.

The two sensory branches of the superficial peroneal nerve: electrophysiological differences and correlations with gender, age, height and BMI.

AIMS OF THE STUDY: To detect amplitude differences between the sensory nerve action potentials (SNAP) obtained by simultaneous recording of the two main branches of the superficial peroneal sensory nerve (SPSN), the medial and intermediate dorsal cutaneous sensory nerves (MDCN, IDCN); to investigate whether these differences, if any, are correlated with gender, age, body mass index (BMI), and height of normal subjects; to discuss their clinical significance. POPULATION AND METHODS: Seventy-six healthy volunteers (36 males) were included (mean age: 36.5 years, range 20-80). Simultaneous MCND and IDCN recordings were performed via surface electrodes placed at precise positions on the intermalleolus line. Stimulation was performed 14 cm proximally on two different sites over the anterolateral aspect of the right leg. RESULTS: Responses were obtained for both nerve branches in all subjects. Median value and lower normal limit for the amplitude of the greater among both MDCN and IDCN responses was 10.95 microV and 4.9 microV, respectively. Statistically significant differences were found between the two branches in median amplitude and frequency of the greater value. These differences were not correlated with gender, age, BMI, or height. CONCLUSION: We propose simultaneous recording of the two main branches of the superficial peroneal sensory nerve, placing the recording electrodes and stimulation device on precise positions and measuring the amplitude of the best of both responses. This method is an improvement of an already existent one, and may be clinically useful in detecting abnormal responses of the SPSN.

Treatment of idiopathic membranous nephropathy (IMN).

The best treatment of idiopathic membranous nephropathy remains an area of clinical controversy. At the moment only patients with nephrotic syndrome and/or declining renal function should be treated. Despite the negative trials, prolonged oral administration of corticosteroids alone may be a safe and an effective first-line treatment in nephrotic patients. If corticosteroids are ineffective, prolonged use of cyclosporine in low-doses can be recommended as an alternative treatment, that diminishes rapidly proteinuria in the majority of patients. Both treatments (intravenous high doses of corticosteroids and cyclosporine) may also be effective in patients with declining renal function. Because of their toxicity, the routine use of alkylating agents for patients with nephrotic syndrome is not justified. They may be retained for patients, in whom other treatment modalities have failed. Chlorambucil may be preferred over cyclophosphamide since it carries less toxicity. A lower dose of chlorambucil, than that usually suggested, for a short period of time seems to be prudent in an effort to avoid serious side-effects.

Is membranous nephropathy only a glomerular disease?

Tubulointerstitial lesions represent not only a constant component of the pathology of a "classical" glomerular disease such as idiopathic membranous nephropathy but also the most important prognostic indicator and a new "target" for its treatment. Proper "quantification" of the cellular events occurring within the interstitium may enable us to accurately assess the amount of disease activity and identify patients who might benefit from treatment.

Factors influencing the course and the response to treatment in primary focal segmental glomerulosclerosis.

BACKGROUND: The clinical course of primary focal segmental glomerulosclerosis (FSGS) varies and there is considerable controversy as to which factors are of importance in determining prognosis or response to therapy. The aim of this study was to identify clinical, pathological or immunohistochemical features at biopsy that could identify patients with progressive disease who might benefit from treatment, and predict long-term outcome. METHODS: The clinical and pathological findings of 33 adult patients with primary FSGS were retrospectively analysed in order to identify features at biopsy that could be predictive of outcome or response to treatment. For this purpose an immunohistochemical study was also performed, using monoclonal antibodies against intracellular adhesion molecules-1, C5b-9, alpha 3 beta 1 integrin, alpha-smooth-muscle actin (SMA), and TGF-beta1. RESULTS: At biopsy 17 patients (51%) were nephrotic and 16 (49%) non-nephrotic. Of the nephrotic patients, 11 were treated and six received only symptomatic therapy. Initial treatment with prednisolone (Pred) for 6-12 months (average 9 months) resulted in remission in 64% of nephrotic patients. To those with partial or no response, cyclosporin (CsA) or cyclophosphamide was given. At the end of follow-up (mean 57 months) three nephrotic patients (28%) were in complete remission, six (54%) in partial remission, and two (18%) did not respond to the treatment. In the seven treated non-nephrotic patients, Pred induced a complete remission in two (28%), a partial remission in three (44%), while two patients (28%) did not respond. Plasma creatinine remained stable in nephrotic patients who responded and it almost doubled in non-responders. Plasma creatinine also remained unchanged in treated non-nephrotic patients who responded to Pred, while two non-responders reached end-stage renal disease (ESRD). In contrast, 50% of untreated nephrotic patients and 67% of untreated non-nephrotic patients progressed to ESRD. Multivariate analysis showed only age and plasma creatinine at biopsy to have an independent predictive value for renal survival in nephrotic patients. This analysis also demonstrated that only the severity of interstitial fibrosis predicted the response to the treatment. In addition, the tubulointerstitial but not the glomerular expression of C5b-9, alpha 3 beta 1 integrin, alpha-SMA, and TGF-beta1 was significantly more extensive in non-responders and correlated with renal function at biopsy. However, only tubulointerstitial expression of TGF-beta1 independently correlated with the degree of renal function impairment at biopsy, but none of the above markers independently predicted renal survival or response to therapy. CONCLUSIONS: Nephrotic patients with FSGS may benefit from a more prolonged course of Pred. Nephrotic patients responding to treatment have a significantly better renal survival than non-responders. Age and plasma creatinine at biopsy are independent risk factors leading to ESRD. The severity of tubulointerstitial fibrosis is predictive of response to therapy.

Adult-onset idiopathic nephrotic syndrome associated with pure diffuse mesangial hypercellularity.

BACKGROUND: Pure diffuse mesangial hypercellularity (DMH), in its primary form, is a relatively rare histological finding and few data exist in the literature regarding its clinical course and prognosis in nephrotic adults with this diagnosis. METHODS: We retrospectively analysed the clinical and histological data of 28 adult nephrotic patients (13 male) with this diagnosis with regard to response to the treatment, outcome and prognostic indicators. RESULTS: Of 25 patients treated with prednisolone (Pred), nine (36%) showed complete remission (CR) of proteinuria, eight (32%) partial remission (PR) and eight (32%) did not respond at all (NR). The combination of cyclosporin treatment with prednisolone of those with PR or NR produced one further complete and two partial remissions. At the end of follow-up (mean 64 months), 10 patients (40%) were in CR, nine (36%) in PR and six (24%) were NR and remained nephrotic. Renal function remained unchanged in patients with CR or PR. In contrast, the six non-responders progressed to end-stage renal disease (ESRD). Compared with non-responders, patients who responded to Pred were older and had normal renal function at presentation. This group also had less mesangial sclerosis and severe tubulointerstitial fibrosis and none showed synechiae with Bowman's capsule. IgM mesangial deposits were observed in 22% of patients with CR in response to Pred, in 37% of those with PR and in 100% of non-responders, who finally progressed to ESRD. A multivariate analysis of clinical and histological features at biopsy showed persistent nephrotic syndrome (P<0.001), the severity of DMH (P<0.03) and the presence of mesangial IgM (P<0. 01) to have independent predictive value for ESRD. This analysis also demonstrated that only mesangial sclerosis (P<0.03) and the presence of mesangial IgM (P<0.002) independently predicted the response to therapy. CONCLUSIONS: DMH associated with idiopathic nephrotic syndrome is a heterogeneous entity. Patients who respond to therapy (completely or partially) have a benign course similar to that of minimal change nephrotic syndrome. They are usually older and have normal renal function at presentation, whereas 'sclerotic' lesions are less frequent findings in initial biopsies. Non-responders tend to be younger and progress to ESRD. Most of them have impaired renal function at first assessment and more prominent 'sclerotic' lesions on initial biopsies. Mesangial IgM is an independent marker of poorer response to treatment and progression to ESRD but it lacks specificity.

Acute renal failure--which treatment modality is the best?

Despite the progress in animal research concerning the pathophysiology and the progress in clinical practice regarding the methods of therapy, the incidence and mortality of acute renal failure remain high, especially when other organs are involved. New pharmacological interventions have led to the perspective that in the near future it may be possible to prevent and/or ameliorate this devastating syndrome. Continuous dialysis therapy and the selection of a biocompatible membrane may possibly help the critically ill patient especially when parenteral nutrition and correction of electrolyte and acid-base disturbances are important. Nevertheless, more solid data are needed and one should take into consideration that acute renal failure is a multifactorial syndrome. The type of dialysis itself is not the only matter which has to be evaluated since the mortality rate can be correlated with the number of involved organs before or after the initiation of acute renal failure and with the severity of the original disease. In clinical practice, a large number of prospective studies and more sophisticated statistical methodology are needed in order to evaluate the proper treatment modality.