Diagnostic specificity of autoantibodies to M-type phospholipase A2 receptor (PLA2R) in differentiating idiopathic membranous nephropathy (IMN) from secondary forms and other glomerular diseases.

Autoantibody against phospholipase A2 receptor (anti-PLA2R) is a sensitive and specific biomarker of idiopathic membranous nephropathy (iMN), being found in approximately 70% of iMN patients and only occasionally in other glomerular diseases. However, whereas its diagnostic specificity vs. normal controls and other glomerulonephritides (GN) has been firmly established, its specificity vs. membranous nephropathy associated with various diseases (sMN) has given inconsistent results. The aim of our study was to evaluate the prevalence of anti-PLA2R antibodies in iMN in comparison with various control groups, including sMN. A total of 252 consecutive iMN patients, 184 pathological and 43 healthy controls were tested for anti-PLA2R antibody using indirect immunofluorescence (PLA2R IIFT, Euroimmun). Anti-PLA2R autoantibodies were detectable in 178/252 iMN patients, 1/80 primary GN, 0/72 secondary GN, 9/32 sMN and 0/43 healthy controls, with a diagnostic sensitivity of 70.6%. The diagnostic specificity of anti-PLA2R antibody vs. normal and pathological controls was 100 and 94.6% respectively. However, when the diagnostic specificity was calculated only vs. secondary forms of MN, it decreased considerably to 71.9%. Interestingly enough, 9 out of 10 anti-PLA2R positive patients in the disease control groups had membranous nephropathy associated with various diseases (7 cancer, 1 Crohn's disease, 1 scleroderma). In conclusion, anti-PLA2R positivity in a patient with MN, should not be considered sufficient to abstain from seeking a secondary cause, especially in patients with risk factors for neoplasia. The causal relationship between tumors and anti-PLA2R-induced MN remains to be established, as well as the possible mechanisms through which malignancies provoke autoimmunity.

Ultrasound findings in dual kidney transplantation.

PURPOSE: This study was done to analyse colour Doppler ultrasound (CDUS) findings in patients with dual kidney transplantation (DKT) and to compare renal volume and resistive index (RI) values between DKT and single kidney transplantation (SKT). MATERIALS AND METHODS: We reviewed the clinical and imaging findings [30 CDUS, five magnetic resonance (MR) and one computed tomography (CT) examination] in 30 patients with DKT (23 men and seven women; median age 65 years; range 55-82). Three patients had clinical signs of graft malfunction. Renal volumes and RI were compared with those of 14 SKT patients and comparable levels of renal function. RESULTS: Three patients had graft dysfunction: one had chronic rejection and two had pathologies involving one kidney only (one encrusted pyeloureteritis of a left graft and one occluded main artery of a left graft). Asymptomatic unilateral pathologies were seen in six cases. In asymptomatic DKT patients, no significant differences in length, volume, cortical echogenicity and RI between the two kidneys were observed; DKTs were smaller (median volume 116.7 vs. 171.6 cc) and had higher RIs (0.76 vs. 0.68) (p<0.01) than SKTs. CONCLUSIONS: CDUS provides useful information in patients with DKT, allowing detection of clinically unsuspected unilateral diseases. At comparable levels of renal function, DKT patients had higher RI and lower volumes than SKT patients.

Long-term outcome on kidney retransplantation: a review of 100 cases from a single center.

Renal transplantation has become an effective form of treatment for end-stage renal failure. Unfortunately, as a consequence of immunological and nonimmunological pathogenic mechanisms, chronic allograft nephropathy is responsible for the loss of a large proportion of kidney grafts after several years and return to dialysis. We have reported herein our 24 years of experience with second kidney transplantations. Of 1,302 kidney transplantations between January 1983 and June 2007 performed in our transplantation center, 100 were second transplantations. Kidney retransplantation was performed in 74 men and 26 women of overall mean age of 35.4 +/- 12.6 years. Cadaveric donor grafts were transplanted in 92 patients, whereas the remaining 8 were living-related donor kidneys. At 1, 5, and 10 years after kidney transplantation, patient survival rates were 100%, 96%, and 92%, respectively, whereas graft survival rates were 85%, 72%, and 53%, respectively. Immunosuppressive therapy included induction therapy with polyclonal anti-lymphocyte antibodies (ALG/ATG) or (starting from 1999) monoclonal anti CD 25 antibody. Our results demonstrated good outcomes for kidney retransplantations with allocation based on anti- HLA antibody identification together with induction immunosuppression.

[Effects of kidney transplantation on bone: osteoporosis or other?]. / Effetti del trapianto di rene sull'osso: osteoporosi o altro?

Post-transplant bone disease is a heterogeneous osteodystrophy because the effects of age, gender, persistent hyperparathyroidism, corticosteroid and calcineurin inhibitor therapy are superimposed. The decrease in bone mass is particularly prominent during the first 6 months after kidney transplantation and is associated with an increased number of fractures. Bone mineral density measurements do not predict bone histology. Bone biopsy reveals heterogeneous lesions, which differ during the early and later phases after transplant. Interestingly, the cases of osteoporosis (BV/TV <15%) are comparatively few, and biopsies in later phases show delayed mineralization as a common finding, and a generalized prevalence of osteomalacic lesions. Bone histology could be a useful tool to delineate the underlying histological alterations in such patients in order to develop adequate therapeutic strategies.

Cytotoxic molecule mRNA expression in chronically rejected human kidney allografts.

The pathogenesis of immunological and nonimmunological components that cause chronic kidney allograft nephropathy (CAN), is not yet completely understood. To explore the possible contribution of alloreactive cytotoxic T cells, we analyzed the transcription of cytotoxic molecules such as granzyme B and perforin using semiquantitative RT-PCR on surgically removed grafts obtained from two groups: group 1 (n = 10) were cases of CAN; group 2 (n = 3) had no CAN. Among group 1 kidneys, granzyme-B was expressed in 7 of 10, whereas perforin was detectable in 9 of 10 cases; their detection was not related to the presence of superimposed signs of acute graft lesions. Cytotoxic molecules were never found in group 2 kidneys. These results show that explanted chronically rejected grafts display cytotoxic molecule transcripts in addition to Th2 type cytokines, such as IL-10, IL-3, and IL-6, suggesting that both cellular and humoral alloreactive mechanisms may play important roles in CAN pathogenesis.

Angiotensin-converting enzyme gene polymorphism and reversibility of uremic left ventricular hypertrophy following long-term antihypertensive therapy.

BACKGROUND: Prolonged antihypertensive therapy might be less effective in reversing the left ventricular hypertrophy (LVH) in uremics bearing the deleted (DD) allele of the angiotensin converting enzyme (ACE) gene than in patients with the inserted (II) allele or in those heterozygous (ID) for the gene. METHODS: Thirteen DD and 17 II + ID hemodialyzed uremics were followed-up with yearly echocardiography and 24-hour blood pressure (BP) monitoring over five years while on an antihypertensive therapy that included ACE inhibitors as first line drugs. RESULTS: In the II + ID group there were significant decreases of the left ventricular mass index (LVMi) and of both systolic and diastolic BPs. These changes were less pronounced in the DD group, but the difference was not statistically significant given the wide overlap between the two groups. Further analysis of the data revealed that the only factor associated to a decreased LVMi was the decrease of the systolic BP irrespective of the ACE gene genotype of each individual patient. CONCLUSIONS: The ACE-gene genotype does not necessarily predict the extent to which LVMi will be lowered by ACE-inhibitors therapy. The LVH of hypertensive uremics is amenable by long-term antihypertensive therapy provided that it results in significantly decreased systolic blood pressure.

Prolonged therapy with ACE inhibitors induces a regression of left ventricular hypertrophy of dialyzed uremic patients independently from hypotensive effects.

Left ventricular hypertrophy (LVH), which frequently occurs in chronic uremia, may be due in part to factors other than arterial hypertension, chronic anemia, and/or other well-known loading conditions inherent to the uremic state. Angiotensin-converting enzyme (ACE) inhibitors may be able to reverse LVH by mechanisms independent of their antihypertensive effects. In this study, 18 subjects free of arterial hypertension or severe anemia were selected from 170 chronically hemodialyzed uremic patients after fulfilling the criterion of a supranormal left ventricular mass (LVM). Ten subjects agreed to undergo treatment with 2.5 to 20 mg lisinopril every other day over a period of 2 years, during which annual determinations of the LVM by echocardiography and of the 24-hour blood pressure with a portable device were carried out. Eight patients unwilling to undergo the treatment served as controls. The average resting left ventricular mass index (LVMi) of the overall group was 178 +/- 30 g/m2 body surface area (+/- SD), and did not differ between the two subgroups. Lisinopril treatment significantly decreased the LVM of eight of 10 treated subjects and actually even completely normalized it in three. The LVM of the untreated group remained unchanged. Systolic and diastolic blood pressures were 138 +/- 5 mm Hg and 78 +/- 6 mm Hg in the treated group and 133 +/- 9 mm Hg and 75 +/- 4 mm Hg in the untreated group, respectively (P = NS), and did not vary over the following 2 years. This study indicates that a mild degree of LVH, which is seemingly independent of arterial blood pressure load, does exist in a tight subset of uremic patients. This study also demonstrates that this type of LVH is apparently nonprogressive. ACE inhibitors given at doses not affecting blood pressure are able to reverse it.

Evidence of healing of secondary hyperparathyroidism in chronically hemodialyzed uremic patients treated with long-term intravenous calcitriol.

The aim of this study was to assess the effect of a long-term course of high-dose i.v. pulses of calcitriol (CLT) on hyperparathyroid bone disease (HBD) and functional mass of parathyroid glands of chronically hemodialyzed uremic (CHU) patients. We prospectively studied nine CHU patients treated with CLT, 30 ng/kg/body wt, i.v., thrice weekly over a period of eight months. Plasma concentrations of intact parathyroid hormone (iPTH), bone GLA protein (bGLA) and bone isoenzyme of alkaline phosphatase (biALP) were sampled throughout. Transiliac bone biopsies were made before and after the start of CLT therapy. Double scanning scintigraphy of the neck with 201Tl-99Tc was made before, during and eight months after the start of the treatment. All patients but one, who later responded to higher than planned CLT doses, had significant decreases of plasma iPTH (F = 76; P < 0.0001; ANOVA). The mean pretreatment value of PTH was 966 +/- 160 (mean +/- SE) pg/ml and it had decreased significantly by the first week (T = 2.4, P < 0.04), and had fallen an average of 80% by the 35th week. Ionized plasma calcium concentration was 1.19 +/- .01 mmol/liter which rose significantly (F = 13.5; P < 0.0001) by the 14th week to maximal peak levels, averaging 1.34 +/- .02 mmol/liter. Changes in biALP were parallel to those of iPTH, while bGLA tended to increase immediately after the start of the therapy and to significantly decrease thereafter (T = 3.2; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in partition of extracellular fluid volumes in anemic dialyzed uremic patients after partial correction of the anemia with recombinant human erythropoietin treatment.

The purpose of this work was to study the effects of correcting anemia on the distribution and partition of body fluids in dialyzed uremic subjects. We studied nine (7 m, 2 f) patients before and three months after the start of i.v. treatment with rHu-EPO, measuring total body water (TBW) with 3H2O, extracellular fluid volume (ECFV) with 35SO4 and plasma volume (PV) with 125I-SA. The intracellular water (ICW) and the interstitial fluid volumes (IFV) were derived by calculation from those measurements. The total blood volume (TBV) was calculated from the PV and the packed cell volume (PCV). Mean TBW, 482 +/- 45 (M +/- SD) ml/kg/bw and ECFV, 168 +/- 27.5 ml were significantly lower in patients than in nine matched normal controls, while the mean ICW (315 +/- 43 ml/kg) was similar. PCV before the start of rHu-EPO was 17.2 +/- 2.9% and had risen significantly to 31.3 +/- 4.8% (p = 0.000) after three months of therapy. Body weight (58 +/- 13 kg), TBW, ECFV and ICW did not change. TBV before rHU-EPO was 68.7 +/- 7.5 ml/kg and remained nearly unchanged, while PV fell significantly from 57 +/- 9 to 48 +/- 8 ml/kg (p < 0.025), with the calculated IFV rising from 111 +/- 25 to 127 +/- 27 (p = 0.000). The PV/IFV ratio decreased from 0.53 +/- 0.12 to 0.38 +/- 0.09 (p = 0.001). The decrease in PV/IFV ratio was paralleled by simultaneous increase in PCV in all but one patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of subcutaneous calcitriol administration on plasma calcium and parathyroid hormone concentrations in continuous ambulatory peritoneal dialysis uremic patients.

OBJECTIVE: To ascertain whether the parathyroid hormone (PTH) secretion of continuous ambulatory peritoneal dialysis (CAPD) uremic patients could be suppressed by repeated subcutaneous injections of calcitriol (CLT). DESIGN: Nonrandomized prospective study with weekly evaluation. SETTING: Hospital CAPD clinic. PATIENTS: Seven uremic CAPD patients with signs of severe hyperparathyroidism. INTERVENTIONS: Patients were treated with CLT (2 micrograms), injected subcutaneously three times a week, on alternate days over a period of 8 weeks. MEASUREMENTS: Plasma PTH, ionized calcium (Ca), serum phosphate (Pi), and alkaline phosphatase (AP) were assayed before the start of CLT therapy and weekly thereafter. RESULTS: The average basal PTH was 349 +/- 26 pg/mL (mean +/- SD). It fell significantly by the fifth week to 158 +/- 20, then leveled off. Analysis of the individual data, however, revealed that only 5 of 7 patients had a significant decrease in plasma PTH. Basal Ca was +/- .02 mmol/L; it increased continuously throughout the study, significantly by the fourth week, reaching a level of 1.33 +/- 0.3 mmol/L at the sixth week, then declined slightly. In those patients with significantly decreased PTH, there was an inverse correlation between PTH and the corresponding Ca levels. CONCLUSIONS: In some CAPD patients subcutaneous administration of CLT significantly suppresses PTH. This effect is mainly mediated via an increase in ionized calcium, but a direct inhibitory effect of the vitamin on parathyroid glands cannot be excluded.

Low-dose intravenous calcitriol treatment of secondary hyperparathyroidism in hemodialysis patients. Italian Group for the Study of Intravenous Calcitriol.

Intravenous calcitriol is known to directly suppress PTH secretion and release. We evaluated the effect of four months of treatment with low-dose intravenous calcitriol on PTH levels in 83 hemodialysis patients. The criteria for including patients in the study were a serum PTH levels at least four times the normal limit, a serum total calcium less than 10 mg/dl and good control of the serum phosphorus level. All patients underwent standard bicarbonate or acetate dialysis; dialysate calcium level was maintained at the usual 3.5 mEq/liter concentration. Initial calcitriol dose was 0.87 +/- 0.02 (SEM) micrograms (0.015 micrograms/kg body wt) thrice weekly at the end of dialysis, and it was reduced in case of hypercalcemia or elevated calcium-phosphate product. Seven out of 83 patients dropped out during treatment. Among the 76 patients who completed the study, 58 (76%) showed a highly significant decrease of intact PTH levels (average reduction 48%) and of alkaline phosphatase levels after four months of therapy. Total serum calcium increased slightly but significantly in the responder group but remained unchanged in the non-responders. No significant changes in ionized calcium levels could be detected, even in responders. Treatment was well tolerated by patients, but 60% of them had transient episodes of hyperphosphatemia. Mean serum phosphate was 4.95 mg/dl at the beginning of the study. It increased significantly after four months of treatment in patients who showed a decrease of PTH levels, although it remained within acceptable limits, below 5.5 mg/dl. Twenty-eight of 76 patients (37%) reduced the dose of calcitriol because their calcium-phosphate products exceeded 60.(ABSTRACT TRUNCATED AT 250 WORDS)

Apheresis for severe malaria complicated by cerebral malaria, acute respiratory distress syndrome, acute renal failure, and disseminated intravascular coagulation.

Malaria has become a very uncommon disease in Italy. Recently a variety of circumstances, such as travel to tropical countries as well as immigration from Asia and Africa, have combined to increase the number of malaria cases recorded annually. In this report we describe the use of red cell exchange transfusion and plasma exchange in the treatment of a patient with hyperparasitemic malaria (51% erythrocytes or more parasitized). When first observed the patient was in shock and had signs of cerebral malaria, disseminated intravascular coagulation, and acute respiratory distress syndrome, which in the following 2 days were complicated by acute renal failure. After mefloquine therapy combined with 3 red blood cell exchanges, 2 plasma exchanges, and 10 dialysis sessions over 14 days, the patient recovered completely. This case of severe malaria with multiple complications, treated with mefloquine in conjunction with both exchange transfusion and plasmapheresis, had a successful outcome and lends further support to the possible beneficial role of exchange transfusion in complicated malaria.