Transforming growth factor-beta(1) in the kidney and urine of patients with glomerular disease and proteinuria.

BACKGROUND: Transforming growth factor-beta(1) (TGF-beta(1)) is the major fibrogenic growth factor implicated in the pathogenesis of renal scarring. Proteinuria is a poor prognostic feature for various types of glomerular disease and its toxic action may be related to the activation of tubular epithelial cells towards increased production of cytokines and chemoattractant peptides. In this work we studied the site of synthesis and expression profile of TGF-beta(1) in the renal tissue of patients with heavy proteinuria and examined the relation of this expression with the urinary excretion of TGF-beta(1). METHODS: Twenty-five patients with heavy proteinuria (8.4+/-3.0 g/24 h) were included in the study. All patients underwent a diagnostic kidney biopsy and were commenced on immunosuppressive therapy with corticosteroids and cyclosporin. The sites of synthesis and expression profile of TGF-beta(1) mRNA and protein in the kidney were examined by in situ hybridization and immunohistochemistry. Urinary and plasma TGF-beta(1) levels were determined by ELISA before the initiation of treatment and 6 months later and compared with those of normal subjects and of patients with IgA nephropathy and normal urinary protein excretion. RESULTS: The site of synthesis and expression of TGF-beta(1) in the renal tissue of patients with heavy proteinuria was mainly localized within the cytoplasm of tubular epithelial cells. Interstitial expression was also present but glomerular TGF-beta(1) expression was found only in patients with mesangial proliferation. Urinary TGF-beta(1) excretion was significantly higher in nephrotic patients compared with normal subjects and with patients with IgA nephropathy and normal urinary protein excretion (783+/-280 vs 310+/-140 and 375+/-90 ng/24 h, respectively; P<0.01). In patients with remission of proteinuria after immunosuppressive therapy, urinary TGF-beta(1) excretion was significantly reduced (from 749+/-290 to 495+/-130 ng/24 h; P<0.01), while in patients with persistent nephrotic syndrome, it remained elevated. CONCLUSIONS: The localization of TGF-beta(1) mRNA and protein within tubular epithelial cells, along with its increased urinary excretion in patients with nephrotic syndrome, suggest the activation of these cells by filtered protein towards increased TGF-beta(1) production.     

The remission of nephrotic syndrome with cyclosporin treatment does not attenuate the progression of idiopathic membranous nephropathy

BACKGROUND: Idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults, is usually treated by combination of corticosteroids with cytotoxic drugs. In cases resistant to this regimen, the use of cyclosporin A (CsA) is followed by frequent remissions of the nephrotic syndrome. AIM: The purpose of this study was to estimate the effectiveness of prednisolone and small doses of CsA as first-line treatment of nephrotic patients with IMN, in relation to the progression of the disease, based on functional and histological changes. PATIENTS AND METHODS: Sixteen patients, with nephrotic syndrome due to IMN and well-preserved renal function, were treated with prednisolone (starting dose: 0.5 mg/kg bw/day) and CsA (starting dose: 3 mg/kg bw/day) for 24 months. A repeat renal biopsy was performed after 18 months of treatment in 10 patients with remission of nephrotic syndrome, to estimate the activity of the disease and to identify any features of CsA toxicity. RESULTS: Remission of the nephrotic syndrome was observed in 14 out of 16 patients after 5 +/- 2 months of treatment. Complete remission was observed in 8 and partial remission in 6 patients (urinary protein was reduced from 6.9 +/- 3.4-0.2 +/- 0.06 g/24 h and 1.2 +/- 1.0 g/24 h, respectively, p < 0.01). The renal function was well preserved in 13 out of 16 patients over a 24-month period of treatment. Deterioration of renal function was observed in 3 patients (creatinine clearance reduced from 86 +/- 21-37 +/- 17 ml/min, p < 0.05) who had either persistent nephrotic syndrome or frequent relapses. Relapses of the nephrotic syndrome were observed in 5 of 14 patients. Repeat renal biopsies showed that glomerular sclerosis, tubulointerstitial injury, vascular hyalinosis and stage of the disease were deteriorated in most patients. Isometric vacuolization of tubular epithelial cells was observed in 2 of 10 patients. CONCLUSION: IMN nephrotic patients treated with prednisolone and low doses of cyclosporin A showed a high remission rate of nephrotic syndrome. However, progression of chronic histological lesions was found in repeat renal biopsies. This suggests that cyclosporin can frequently induce remission of nephrotic syndrome in IMN patients, but even low doses of the drug are not free of potential renal toxicity.     

Microchimerism in Peripheral Blood and Urine in Renal Transplant Recipients: Preliminary Results

The role of microchimerism in peripheral blood and urine of renal transplant recipients remains a matter of debate, depending on the sensitivity of the methods used for detection. We studied 17 female renal transplant recipients who had received renal allografts from male donors. Polymerase chain reaction (PCR) was applied to blood and urine for the microsatellite markers D1S80, DYZ1, TH01, and kαi SE33. Detection of DYZ1 that is present only on the Y chromosome was considered proof for microchimerism. No microchimerism was detected in peripheral blood, whereas it could be detected in the urine of 8/17 (48%) patients. There were no differences between patients with and without microchimerism regarding patient age, dialysis vintage, immunosuppression, time post-transplantation, and allograft function as measured using serum creatinine, creatinine clearance, and proteinuria. Two patients in each group showed chronic allograft dysfunction. These findings raise questions regarding the role of microchimerism in renal transplantation.     

Cyclosporin-A in the treatment of nephrotic syndrome: the importance of monitoring C0 (trough) and C2 (two hours after its administration) blood levels

Cyclosporin-A (CsA) is often used in the treatment of nephrotic syndrome. The effectiveness of CsA and the value of C2 blood levels in the treatment of nephrotic syndrome, due to various glomerular diseases, were studied. Forty-two nephrotic patients (M/F 21/21), with well-preserved renal function (creatinine clearance 87+/-20 ml/min) were included in the study. The original diagnoses were minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), and lupus nephritis (LN). All patients were treated with prednisolone and CsA for 24 months. Cyclosporin-A C0 and C2 blood levels were determined at regular intervals. Remission of the nephrotic syndrome was observed in all patients with MCD, IgAN and LN, in 75% with FSGS and in 83% with MN. Relapses were observed in some patients with MCD (25%) and MN (36%). The C0 levels were 93+/-15 ng/ml and the corresponding C2 levels were 498+/-110 ng/ml. However, significantly lower (340+/-83 ng/ml) or higher (680+/-127 ng/ml) to the average C2 levels were found in 6 patients (14%). No relation of C0 and C2 levels with the remission and relapse rate of the nephrotic syndrome and with renal function impairment was observed. Small doses of CsA with prednisolone are effective in the treatment of nephrotic syndrome. Although an individual variation of C2 was observed for the same target C0 levels, no relation of C2 levels was found with the remission or relapse rate of the nephrotic syndrome.     

Auditory nerve is affected in one of two different point mutations of the neurofilament light gene.

OBJECTIVE: To define auditory nerve and cochlear functions in two families with autosomal dominant axonal Charcot-Marie-Tooth (CMT). METHODS: Affected members in two families with different point mutations of NF-L gene were screened with auditory brainstem responses (ABRs). Those with abnormal ABRs were further investigated with clinical, neurophysiological and audiological procedures. The point mutations of NF-L gene involved were Glu397Lys in 8 affected members of the family with AN, and Pro22Ser in 9 affected members of the family without AN. RESULTS: ABRs and stapedial muscle reflexes were absent or abnormal in affected members of only one family consistent with auditory neuropathy (AN). In them, audiograms, otoacoustic emissions, and speech comprehension were normal. Absent or abnormal ABRs were consistent with slowing of conduction along auditory nerve and/or brainstem auditory pathway. Wave I when present was of normal latency. CONCLUSIONS: Auditory nerve involvement in the presence of normal cochlear outer hair cell activity is asymptomatic in one of two families with CMT disorder with different point mutations of the NF-L gene. The nerve disorder is consistent with altered synchrony and slowed conduction. SIGNIFICANCE: The absence of "deafness" may reflect the ability of central mechanisms to compensate for the slowly developing auditory nerve abnormalities.     

A novel<Emphasis Type="Italic"> PMP22</Emphasis> mutation Ser22Phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes

We describe a Cypriot family in which some family members presented with episodes of pressure palsies, while other family members had a slowly progressive chronic polyneuropathy typical of the Charcot-Marie-Tooth type 1 phenotype. All family members were evaluated clinically, with nerve conduction studies, and with genetic testing. In all affected individuals there was clinical and electrophysiological evidence of diffuse demyelinating sensorimotor polyneuropathy and a novel point mutation in the PMP22 gene (Ser22Phe) was identified.     

Cyclosporin A in adult patients with Henoch-Schönlein purpura nephritis and nephrotic syndrome; 5 case reports

Henoch-Sch?nlein purpura (HSP) is usually followed by mild renal involvement, but heavy proteinuria may also occur. Limited experience with cyclosporin A in children shows reduction of proteinuria. In this report, the use of cyclosporin A in 5 adult HSP patients with nephrotic-range proteinuria is described. Cyclosporin A in combination with prednisolone was given in 3 patients with HSP nephritis and nephrotic syndrome after a course of other immunosuppressive drugs and in 2 patients as initial treatment. All patients showed complete or partial remission of nephrotic syndrome with cyclosporin A and preserved stable renal function over a follow-up period of 5 years. We conclude that the combination of cyclosporin A with corticosteroids is effective in inducing remission of nephrotic syndrome in adult patients with HSP nephritis.     

Outcome of Transplantation in Renal Allograft Recipients From Cadaveric Donors With Standard and Expanded Criteria: A Single-Center Experience

IntroductionThe increasing number of patients requiring kidney transplantation and the lack of available organs has led to the utilization of kidneys from expanded criteria donors (ECD).AimThe comparison of the clinical outcome of renal transplantation, performed in a single center, between allograft recipients from standard (SCD) and expanded criteria donors (ECD).Patients and MethodsData from 215 cadaveric renal transplantations performed during a 16 year period at the University Hospital of Patras were retrospectively studied. Donors' and recipients' characteristics (gender, age, history of hypertension and diabetes mellitus, cold ischemia time, post-transplant and long term graft function) were analyzed.ResultsGrafts from donors with expanded criteria (ECD, n = 53) were allocated to older recipients whereas grafts from donors with standard criteria (SCD, n = 162) were allocated to younger recipients. The mean cold ischemia time was 1,146 min and was similar between the two groups of patients. Patients' survival rates were similar between allograft recipients from SCD and ECD up to the 5^th post-transplant year of follow-up. Graft survival was significantly better in allograft recipients from SCD during a 5-year follow-up period. A significantly lower eGFR was noted in allograft recipients from ECD in comparison to those from SCD throughout the observation period. Cold ischemia time was positively correlated to the development of DGF, while patients with DGF had significantly worse graft function throughout the observation period.ConclusionPatient survival from ECD is comparable to that from SCD but graft survival is significantly lower. However, since renal function of recipients from ECD is adequate for long term period, grafts from ECD should be used in older patients.     

Parameters Influencing Blood Erythropoietin Levels of Renal Transplant Recipients During the Early Post-transplantation Period

AimRenal transplantation is accompanied by restoration of renal function and endogenous erythropoietin production. The purpose of this study was to investigate the time-related changes of endogenous erythropoietin secretion in the early renal post-transplant period and the influence of various parameters to this process.MethodsFifty-eight patients were enrolled in the study and followed up for 3 months after successful renal transplantation. Erythropoietin levels were measured at regular intervals and correlated with renal function, cold ischemia time and immunosuppressive regimen used.ResultsTwo peaks of serum erythropoietin levels were observed: an early peak that occurred within two days after transplantation and a late one, between weeks 2 and 4, which resulted in increased blood hemoglobin levels. Factors that were found to correlate with erythropoietin levels were delayed graft function, cyclosporine use and prolonged cold ischemia time. Serum creatinine did not correlate to erythropoietin levels although the reduction of serum creatinine preceded the rise of erythropoietin levels. Normal hemoglobin values were restored about three months after successful renal transplantation.ConclusionSerum erythropoietin levels increase during the early post-transplantation period resulting in correction of anemia three months after a successful renal transplantation. Restoration of allograft function is a prerequisite for erythropoietin secretion, while cold ischemia time and immunosuppressive regimen affect graft function.     

Benefit and cost from the long-term use of cyclosporine-A in idiopathic membranous nephropathy

Aim: Idiopathic membranous nephropathy (IMN), the most common cause of nephrotic syndrome in adults, is usually treated by cyclosporin A (CsA). Estimation of the effectiveness of long‐term use of CsA in the remission and relapse rate of nephrotic syndrome along with histological changes in repeat renal biopsies was the aim of the study. Methods: Thirty‐two nephrotic patients with well‐preserved renal function treated by prednisolone and CsA were studied. A repeat biopsy was performed in 18 patients with remission of nephrotic syndrome, after 24 months of treatment, to estimate the activity of the disease and features of CsA toxicity. Results: Complete remission of nephrotic syndrome was observed in 18 (56%) and partial remission in 10 patients (31%) after 12 months of treatment (total 87%). Relapses were observed in 39% and 60% of patients with complete and partial remission, respectively, and multiple relapses in 25% of patients, who showed gradual unresponsiveness to CsA and decline of renal function. Progression of stage of the disease and more severe glomerulosclerosis and tubulointerstitial injury were recognized in 55% and 61% of patients respectively. Features of CsA nephrotoxicity were not observed. The severity of histological changes was related to the time elapsed from the first biopsy (r = 0.452, P < 0.05). Conclusion: Low doses of CsA with prednisolone induce remission of nephrotic syndrome in most idiopathic membranous nephropathy patients. Although typical features of CsA nephrotoxicity are not observed, significant deterioration of histological lesions occurs with time, even in patients with remission. Long‐term use of CsA should be examined with caution.