The use of pulse wave velocity in predicting pre-eclampsia in high-risk women.

In this study, we evaluated the diagnostic utility of pulse wave velocity (PWV) alone or in combination with other diagnostic markers in predicting pre-eclampsia (PE) in high-risk women. Pregnant women at high risk for PE were recruited between 22 and 26 weeks of gestation and were assessed for (a) PWV, (b) serum levels of the placental soluble fms-like tyrosine kinase 1 (sFlt-1) protein and uric acid and (c) 24-h urinary protein and calcium excretion. Sensitivities and specificities were derived from receiver operating characteristic curves. Of 118 women recruited, 11 and 10 women developed early-onset PE (<34 weeks) and late-onset PE (≥34 weeks), respectively. Of the five diagnostic markers tested, PWV showed the highest detection rate for all cases (21) of PE (81%) and for early-onset PE (82%) at a fixed 10% false-positive rate (FPR), and when combined with sFlt-1, these figures increased to 90% and 92%, respectively. Despite the reduced ability of PWV to predict late-onset PE (detection rate 20%), the combination of PWV with sFlt-1 achieved a detection rate of 50% at a fixed 10% FPR. A suggested cutoff value of 9 m/s for PWV resulted in optimal sensitivity (91%) and specificity (86%) for predicting early-onset PE. This study is the first to show that PWV may be a potentially promising predictor of early-onset PE in women at high risk for PE. The combination of PWV with sFlt-1 may further improve the screening efficacy for predicting PE.

Rapamycin ameliorates proteinuria and restores nephrin and podocin expression in experimental membranous nephropathy.

OBJECTIVE: Recent studies have shown a beneficial effect of rapamycin in passive and active Heymann Nephritis (HN). However, the mechanisms underlying this beneficial effect have not been elucidated. METHODS: Passive Heymann Nephritis (PHN) was induced by a single intravenous infusion of anti-Fx1 in 12 Sprague-Dawley male rats. One week later, six of these rats were commenced on daily treatment with subcutaneous rapamycin 0.5 mgr/kg (PHN-Rapa). The remaining six rats were used as the proteinuric control group (PHN) while six more rats without PHN were given the rapamycin solvent and served as the healthy control group (HC). All rats were sacrificed at the end of the 7th week. RESULTS: Rapamycin significantly reduced proteinuria during the autologous phase of PHN. Histological lesions were markedly improved by rapamycin. Immunofluorescence revealed attenuated deposits of autologous alloantibodies in treated rats. Untreated rats showed decreased glomerular content of both nephrin and podocin whereas rapamycin restored their expression. CONCLUSIONS: Rapamycin monotherapy significantly improves proteinuria and histological lesions in experimental membranous nephropathy. This beneficial effect may be mediated by inhibition of the alloimmune response during the autologous phase of PHN and by restoration of the normal expression of the podocyte proteins nephrin and podocin.

Hsf-1 affects podocyte markers NPHS1, NPHS2 and WT1 in a transgenic mouse model of TTRVal30Met-related amyloidosis.

INTRODUCTION: Familial amyloid polyneuropathy is characterized by transthyretin (TTR) deposition in various tissues, including the kidneys. While deposition induces organ dysfunction, renal involvement in TTR-related amyloidosis could manifest from proteinuria to end-stage kidney failure. As proteinuria is considered result of glomerular filtration barrier injury we investigated whether TTR deposition affects either glomerular basement membrane (GBM) or podocytes. MATERIALS AND METHODS: Immunohistochemistry, immunoblot and gene expression studies for nephrin, podocin and WT1 were run on renal tissue from human-TTRV30M transgenic mice hemizygous or homozygous for heat shock factor one (Hsf-1). Transmission electron microscopy was used for evaluation of podocyte foot process width (PFW) and GBM thickness in Hsf-1 hemizygous mice with or without TTRV30M or amyloid deposition. RESULTS: Glomeruli of hsf-1 hemizygous transgenic mice showed lower nephrin and podocin protein levels but an increased podocyte number when compared to Hsf-1 homozygous transgenic mice. Nephrin, podocin and WT1 gene expression levels were unaffected by the Hsf-1 carrier status. TTRV30M deposition was associated with increased PFW and GBM thickness. CONCLUSIONS: Under the effect of Hsf-1 hemizygosity, TTRV30M deposition has deleterious effects on GBM thickness, PFW and slit diaphragm composition, without affecting nephrin and podocin gene expression.

Losartan affects glomerular AKT and mTOR phosphorylation in an experimental model of type 1 diabetic nephropathy.

The AKT-mTOR pathway is activated in diabetic nephropathy. Renin-angiotensin system modulators exert beneficial effects on the diabetic kidney. We explored the action of losartan on AKT-mTOR phosphorylation in glomeruli and podocytes. Diabetes mellitus was induced to Sprague-Dawley rats by streptozotocin. Five months later, the rats were commenced on losartan and euthanized 2 months later. Kidneys were processed for immunofluorescence studies. Glomeruli were isolated for Western blot analysis. Diabetes increased activated forms of AKT and mTOR both in glomeruli and podocytes. In diabetic rats, losartan decreased phosphorylated/activated forms of AKT (Thr308) and mTOR (Ser2448) in glomeruli but decreased only activated mTOR in podocytes. However, in both glomeruli and podocytes of healthy animals, an inverse pattern was evident. In conclusion, a new body of evidence indicates the differential activation of AKT-mTOR in glomeruli and podocytes of healthy and diabetic animals in response to losartan.

Human TTRV30M localization within podocytes in a transgenic mouse model of transthyretin related amyloidosis: does the environment play a role?

Transthyretin related amyloidosis is a nosological entity that leads to disability, diminished quality of life, all stages of chronic kidney disease and eventually death. Podocytes are polarized, highly differentiated epithelial cells important for proper nephron function. In the present study we investigated whether deposited TTRVal30Met (TTRV30M) molecules could be localized within podocytes in situ under the effect of different housing conditions (i.e. specific pathogen free [SPF] vs. non-SPF). Murine renal glomeruli from human TTRV30M (hTTRV30M) transgenic mice were examined via direct and indirect immunofluorescence techniques for the presence of hTTRV30M, murine serum amyloid P, activated caspase-3 and NPHS1. Association strength and amount of colocalization for NPHS1-hTTRV30M, NPHS1-activated caspase-3, hTTRV30M-murine serum amyloid P were estimated. Localization of hTTRV30M in podocytes was demonstrated by immuno-electron microscopy. Renal hTTRV30M gene and NPHS1 gene expression levels were estimated. Non-SPF transgenic mice showed increased glomerular hTTRV30M deposition compared to their SPF counterparts. Furthermore increased podocytic localization of hTTRV30M was noticed in non-SPF mice. Glomerular caspase-3 activation was increased only in the non SPF housing conditions. Podocytic caspase-3 activation was increased in SPF and in non-SPF transgenic mice when compared to non transgenic controls. Environmental conditions influence glomerular deposition and podocytic localization of hTTRV30M. In this context increased caspase-3 activation occurred.

Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice.

BACKGROUND: In the normal kidney, rapamycin is considered to be non-nephrotoxic. In the present study, we investigated whether rapamycin is indeed non-nephrotoxic by examining the ultrastructural and molecular alterations of podocytes in healthy mice. METHODS: Balb/c mice were given three different intraperitoneal doses of rapamycin for 1 week (dose model)-low-dose group: 1 mg/kg/day, intermediate-dose (ID) group: 1.5 mg/kg/day and high-dose (HD) group: 3 mg/kg/day; four mice in each group. An ID of rapamycin was also given for three different periods (time model): 1, 4 and 8 weeks; four mice were in each group. Mice treated with dimethyl sulphoxide served as controls. Body weight was measured weekly. Renal function was assessed by serum creatinine at the time of sacrifice. For estimation of albuminuria, 24-h urine collections were performed before treatment and weekly thereafter. Glomerular content of nephrin, podocin, Akt and Ser473-phospho-Akt was estimated by western blot and immunofluorescence. Nephrin and podocin messenger RNA (mRNA) were measured by real-time polymerase chain reaction. Mean podocyte foot process width (FPW) was measured by electron microscopy. RESULTS: Urine albumin levels increased in the HD and 4-week groups. Renal function was modestly deteriorated in the HD group. The mean FPW increased in a dose-dependant manner at Week 1, further deteriorated at Week 4 and finally improved at Week 8. Nephrin and podocin mRNA levels showed a significant decrease at Week 1 and were restored at Week 4 and 8. Nephrin and podocin protein levels were reduced at Week 4 and recovered at Week 8. Ser473-phospho-Akt significantly increased in all rapamycin-treated groups. CONCLUSIONS: Rapamycin induced significant ultrastructural and molecular alterations in podocytes in association with albuminuria. These alterations happened early during treatment and they tended to improve over an 8-week treatment period.

The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin.

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, has been shown to inhibit the progression of murine lupus nephritis by virtue of its potent immunosuppressive properties. The phosphoinositol-3-kinase (PI3K)/Akt pathway is a major upstream activator of mTOR and has been implicated in the propagation of cancer and autoimmunity. However, the activation status of the PI3K/Akt/mTOR pathway in lupus nephritis has not been studied so far. METHODS: In NZBW/F1 female mice, we examined the glomerular expression of Akt and mTOR by immunofluorescence and western blot. We also searched for specific phosphorylations of these kinases known to ensue during activation of the PI3K/Akt/mTOR pathway. In parallel, we examined the therapeutic role of rapamycin either before or after the development of overt lupus nephritis. RESULTS: We found that in untreated mice, as opposed to healthy controls, Akt and mTOR were over-expressed and phosphorylated at key activating residues. Rapamycin prolonged survival, maintained normal renal function, normalized proteinuria, restored nephrin and podocin levels, reduced anti-dsDNA titres, ameliorated histological lesions, and reduced Akt and mTOR glomerular expression activation. CONCLUSIONS: These results suggest that: (i) the PI3K/Akt/mTOR pathway is upregulated in murine lupus nephritis, thus justifying treatment with rapamycin; (ii) rapamycin not only blocks mTOR but also negatively regulates the PI3K/Akt/mTOR pathway; and (iii) rapamycin is an effective treatment of murine lupus nephritis. Examination of the PI3K/Akt/mTOR pathway may offer new insights into the pathogenesis of lupus nephritis in humans and may lead to more individualized and less toxic treatment.

Membranous nephropathy and lupus-like syndrome after hematopoietic cell transplantation: a case report.

INTRODUCTION: The kidney is increasingly recognised as a target organ of chronic graft-versus-host disease after hematopoietic cell transplantation in the context of the development of the nephrotic syndrome. Chronic graft-versus-host disease is associated with autoimmune phenomena similar, but not identical, to those observed in various rheumatologic disorders, implicating autoimmunity as an important component of the disease. CASE PRESENTATION: We report the case of a 57-year-old Caucasian man who developed the nephrotic syndrome due to membranous nephropathy in association with recurrent chronic graft-versus-host disease, along with a lupus-like syndrome manifested with pancytopenia, hair loss, positive anti-DNA antibodies and sub-epithelial and mesangial immune deposits. To the best of our knowledge, this is the first case reported in the literature. The nephrotic syndrome subsided soon after he was treated with a short course of cyclosporin with steroids. Unfortunately he died seven months later due to a relapse of leukemia. CONCLUSIONS: Our case report confirms the notion that chronic graft-versus-host disease is characterized by the appearance of autoimmune phenomena similar, but not identical, to those seen in autoimmune diseases. The decision for more immunosuppression has to be weighed against the need for preservation of the graft versus leukemia phenomenon.

Biopsy-proven resolution of renal light-chain deposition disease after autologous stem cell transplantation.

Light-chain deposition disease (LCDD) is caused by an underlying clonal plasma cell dyscrasia in which monoclonal immunoglobulin light chains (LCs) are deposited in tissues, resulting in varying degrees of organ dysfunction. Autologous stem cell transplantation (ASCT) has been reported to stabilize renal function in patients with LCDD, but currently, no evidence of histopathologic resolution of LC deposition after ASCT exists. We present a patient, with severe renal dysfunction due to LCDD, who was treated with high-dose melphalan and ASCT that resulted in a significant and extended period of improved renal function. Four years after the initial improvement, the patient developed nephrotic range proteinuria, without any evidence of relapse of the plasma cell dyscrasia. At that time, a repeat renal biopsy showed complete resolution of LC depositions and development of extensive glomerulosclerosis, thus explaining proteinuria. To the best of our knowledge, this is the first report of a biopsy-proven resolution of renal LCDD following ASCT. A timely application of ASCT should be considered in LCDD to prevent deterioration of renal function in the long run.

Refractory thrombotic thrombocytopenic purpura associated with oral contraceptives and factor V Leiden: a case report.

INTRODUCTION: Thrombotic microangiopathies constitute a heterogeneous group of diseases characterised by microangiopathic haemolytic anaemia and thrombocytopaenia associated with platelet aggregation in the microcirculation responsible for ischaemic manifestations. Classically, thrombotic microangiopathies are described as encompassing two main syndromes: thrombotic thrombocytopaenic purpura and the haemolytic-uraemic syndrome Many cases of idiopathic thrombotic thrombocytopaenic purpura have, to date, been associated with severe ADAMTS13 metalloprotease deficiency while haemolytic uraemic syndrome usually occurs in the context of normal protease activity. Oestrogens and factor V Leiden have rarely been implicated in the pathogenesis of thrombotic microangiopathy. CASE PRESENTATION: We describe the case of a 17-year-old female with refractory thrombotic thrombocytopaenic purpura. The patient was receiving a new generation of oral contraceptives for dysmenorrhoea and had factor V Leiden. After undergoing prolonged and intense plasma exchange therapy for 40 days and high dose oral corticosteroids therapy for 90 days, our patient recovered fully. CONCLUSION: Patients with refractory thrombotic thrombocytopaenic purpura should likely be evaluated for congenital thrombophilic disorders and for ingestion of drugs that have been associated with this rare form of thrombotic microangiopathy. Identification of these and as yet other unknown genetic and/or acquired risk factors may lead to more judicious treatment approaches.

Long-term complication rates and survival of peritoneal dialysis catheters: the role of percutaneous versus surgical placement.

Considerable controversy currently exists in the literature concerning the mode of catheter placement and its impact on the technical success of peritoneal dialysis (PD). We decided to compare the impact of the surgical versus the percutaneous insertion technique on peritoneal dialysis catheter (PDCs) complications and survival. Our study population comprised 152 patients in whom 170 PDCs were inserted between January 1990 and December 2007 at the main PD unit on the island of Crete. Eighty four catheters were surgically placed (S group) and 86 were placed percutaneously by nephrologists (N group). The total experience accumulated was 4997 patient-months. The overall complications did not differ between the two groups. Only early leakage was more frequent in N group than S group (10.3 versus 1.9 episodes per 1000 patient-months; p < 0.001). However, it was easily treated and did not constitute a cause of early catheter removal. Catheter survival was 91.1%, 80.7%, and 73.2%, in the S group versus 89.5%, 83.7%, and 83.7% for the N group at 1, 2, and 3 years, respectively (p = 0.2). Catheter survival has significantly increased over the last decade. Factors positively affecting PDC survival appeared to be the use of mupirocin for exit site care and the utilization of the coiled type of catheter, practices implemented mainly after 1999. Peritonitis-free survival and patient survival were not associated with the mode of placement, while in Cox regression analysis, were longer in patients treated with automated PD. The placement mode did not affect PD outcomes. Percutaneous implantation proved a safe, simple, low cost, immediately available method for PDC placement and helped to expand our PD program.

Percutaneous ethanol injection therapy: a surgery-sparing treatment for primary hyperparathyroidism.

OBJECTIVE: To describe our 3-year experience in the long-term efficacy and safety of percutaneous ethanol injection therapy (PEIT), as an alternative to surgery for the management of patients with primary hyperparathyroidism (p-HPT). DESIGN: Prospective study with a mean follow-up of 19.6 +/- 10.6 months. PATIENTS: Our study population included 19 consecutive high risk patients with p-HPT, who met the criteria for surgery. MEASUREMENTS: Under ultrasonic guidance, ethanol (95%) was injected into parathyroid glands with a volume of >or= 0.15 cm(3). With the aim of normalizing intact parathormone (iPTH) values, repeated ethanol injections were carried out, in an interval of 2 weeks, until normalization of iPTH was reached or until no residual blood supply was detected by ultrasound in the gland. Biochemical parameters were monitored throughout the study. RESULTS: At 6-month follow-up, normalization of iPTH levels (10-65 ng/l) was achieved in 11 (58%) patients (responders). Of the eight remaining patients (nonresponders), six patients had reduced (but not normalized) iPTH levels and two patients required parathyroid surgery. Seventeen (11 responders and 6 nonresponders) of the 19 patients (89.5%) became normocalcaemic (serum Ca 200 ng/l. The only complication was a transient dysphonia noticed in three patients. CONCLUSIONS: PEIT is a safe and effective nonsurgical treatment for patients with p-HPT, who are unsuitable for surgical intervention.

Acute renal failure, translocational hyponatremia and hyperkalemia following intravenous immunoglobulin therapy.

BACKGROUND/AIMS: Intravenous immunoglobulin (IVIG) therapy has been associated with renal adverse effects and electrolyte disturbances. METHODS: We retrospectively evaluated a cohort of 66 unselected patients with idiopathic thrombocytopenic purpura, who received 140 courses of IVIG therapy. Acute renal failure (ARF), hyponatremia and hyperkalemia, as potential complications of IVIG therapy, were assessed from 100 IVIG courses with sufficient data for analysis. RESULTS: Thirteen out of 100 (13%) IVIG courses in 10 (15%) patients were complicated with ARF. Risk factors included advanced age, pre-existing renal impairment, use of diuretics and the presence of diabetes mellitus. All patients recovered renal function 1-2 weeks after IVIG infusion. Serum sodium (sNa) fell by 5.7 and 2.7 mmol/l (p < 0.01) in patients with and without ARF, respectively. Correspondingly, serum potassium increased by 0.7 and 0.23 mmol/l (p < 0.01). There was a strong inverse correlation (r = -0.308; p < 0.01) between changes in sNa and creatinine. Changes in serum potassium could be independently predicted by changes in both sNa and creatinine (R(2) = 0.11; p < 0.01). These data suggested that both hyponatremia and hyperkalemia were (a) due to the translocational effect of the osmotic load of sucrose, and (b) largely depended on the extent of IVIG nephropathy. CONCLUSION: In our series, ARF attributable to IVIG therapy, although not rare, was usually mild and fully reversible. High-risk patients were more susceptible to IVIG-related renal complications. Translocational hyponatremia and hyperkalemia following IVIG therapy, although unimportant in patients with normal renal function, may be of clinical significance in patients with severely compromised renal function, resulting in impaired sucrose excretion.

Corticosteroids and ciclosporin A in idiopathic membranous nephropathy: higher remission rates of nephrotic syndrome and less adverse reactions than after traditional treatment with cytotoxic drugs.

BACKGROUND/AIM: Idiopathic membranous nephropathy, the most common cause of nephrotic syndrome in adults, has been traditionally treated with corticosteroids and cytotoxic drugs. Ciclosporin A (CsA) is used in resistant cases, but also as a first-line treatment, due to the serious side effects of cytotoxic drugs. In this study, the remission rates of nephrotic syndrome and the incidence of side effects of corticosteroids and low CsA doses are compared with those after treatment with cytotoxic drugs. METHODS: Seventy-seven nephrotic patients with well-preserved renal function who were treated with methylprednisolone and CsA (n = 46) or cytotoxic drugs (n = 31) were studied. The effects of treatments were estimated on the basis of remission rates of nephrotic syndrome and preservation of the renal function. RESULTS: Remission (complete or partial) of nephrotic syndrome was observed in 85% of the patients treated with CsA and in 55% of the patients treated with cytotoxic drugs (p < 0.01). Deterioration of the renal function, more common in patients with multiple relapses and interstitial fibrosis, was observed in 26 and 23% of the patients, respectively (p = NS). Serious side effects and discontinuation of treatment were more frequent in patients treated with cytotoxic drugs (10 vs. 4%). CONCLUSION: The combination of corticosteroids with CsA represents a better regimen for patients having idiopathic membranous nephropathy, since it is associated with higher remission rates of nephrotic syndrome and less severe side effects than corticosteroids and cytotoxic drugs.

Can a left internal jugular catheter be used in the hemodialysis of a patient with persistent left superior vena cava?

A patient with a persistent left superior vena cava (PLSVC) was incidentally diagnosed after positioning of a dual lumen catheter for hemodialysis into the left internal jugular vein. Although PLSVC is a relatively rare condition, it is the most common congenital anomaly of thoracic venous circulation. It represents the persistence of the left horn of the embryonic sinus venosus, which normally involutes during embryogenesis to become the coronary sinus. The existence of a PLSVC can cause a significant diagnostic dilemma during catheterization of the left internal jugular vein, pertaining to the positioning of the catheter. It may also be associated with significant clinical implications such as systemic embolization, provocation of arrhythmia, and thrombosis of the vessel. The safety of such catheterization has not been adequately evaluated due to the rarity of this condition. We believe that a diagnostic workup including blood gas analysis, echocardiography, and computed tomography is necessary to confirm a right atrial drainage and a patent innominate vein as prerequisites to maintain the catheter in position.