[Experimental pancreatic islet transplant into the genito-urinary tract simultaneous to kidney transplant]. / Trasplante experimental de islotes de pancreas en el tracto genitourinario asociado al trasplante renal.

INTRODUCTION AND OBJECTIVES: Simultaneous kidney and pancreas transplant is a good treatment for both renal and pancreas insufficiency. Experimental apply of genitourinary tract for pancreas implantation is reported in this work. MATERIAL AND METHOD: Twenty animals aged as average 5.5 monts (SD 1.1) and an average weight of 53 kgr were submitted to this protocol. In the day 1 a left nephrectomy is completed and the graft is perfused with University of Wisconsin solution. A partial pancreatectomy is completed at following, isolation of pancreatic islets by colagenase enzymatic digestion. Islets are dryed with Ditizone and culptured for 24 hours at 37 degrees C and 5% CO2. Day-2 a right nephrectomy is performed and orthotopic renal autotransplant using the left kidney is completed. Pancreatic islets are transplanted in 4 different locations of the genitourinary tract: renal subcapsular space, bladder submucosae, testis parenchyma and vas deferens. Day-7, all the animals were sacrifized to complete pathological study. RESULTS AND CONCLUSIONS: Viable islets were isolated in bladder submucosae and testis after transdeferential injection.

Recurrent acute postinfectious glomerulonephritis.

Recurrent acute postinfectious glomerulonephritis is infrequent in childhood and exceptional in adults. The factors that determine recurrence are poorly understood. Selective IgA deficiency is characterized by an increased incidence of gastrointestinal and respiratory infections. The case of a 33-year-old man with a history of repetitive sinopulmonary infections and diagnosed with selective IgA deficiency is described. He suffered 2 episodes of postinfectious glomerulonephritis within a 15-year period. Selective IgA deficiency may have predisposed to the development of recurrent postinfectious glomerulonephritis

Pancreas islet transplantation in the genitourinary tract associated with renal transplantation: an experimental study.

Conceptually, pancreas islet transplantation (PIT) associated with renal transplantation (RT) should resolve not only chronic renal failure but also diabetes. Although the most frequently used site for PIT is the portal vein, genitourinary locations could be technically feasible during RT. Seventeen pigs (age 3 to 4 months; mean weight 34.5 kg) underwent the following experimental steps: On day 1 a left nephrectomy was performed and the kidney was perfused with cold Wisconsin solution. This was followed by a caudal pancreatectomy and islet isolation by means of digestion with intraductal collagenase. Islets were stained with Dithizone and cultured overnight al 37 degrees C and 5% CO(2). On day 2 a right nephrectomy and orthotopic RT of the preserved left kidney were performed. The islets were transplanted into four different sites: subcapsular in the kidney graft, in the bladder submucosa, in the testis by puncture, and in the testis by infusion through the vas deferens. On day 7 the animals were sacrificed. Islet viability was determined by histological examination with insulin immunostaining and determination of insulin in the blood of the veins draining the implantation sites. The mean weight of the pancreatic specimens was 27.8 g (13 to 46). The mean number of islets was 536,000 (16,600 to 1,5000,000). Islets were shown in the bladder submucosa and the testes after vas deferens infusion. The number of viable islets in the other implantation sites was very scarce. The insulin levels of the venous effluents were: 15.1 microU/mL for bladder submucosa, 10.2 microU/mL for intradeferential injection in the testis, 7.3 microU/mL for intratesticular injection by puncture, and 2.6 microU/mL for subcapsular implantation in the graft. In conclusion, the bladder submucosa and testis via the vas deferens might represent alternative sites for PIT. The latter route may benefit from the immunoprivileged and special trophic conditions of the testis. For the first time, the feasibility of the bladder submucosa as an implantation site for pancreas islets was demonstrated.

[Tubulointerstitial nephritis associated with treatment with selective Cox-2 inhibitors, celecoxib and rofecoxib]. / Nefritis tubulointersticial asociada al tratamiento con inhibidores de la Cox-2, celecoxib y rofecoxib.

The nephrotoxic effect of nonselective nonsteroidal anti-inflamatory drugs (NSAIDS) has been widely described. The main benefit of the Cox-2 inhibitors in relation to the NSAIDS is the production of a very similar analgesic effect, but with fewer gastrointestinal side effects. However, their effects on renal function are little known as yet and their long-term safety is still pending definition. The use of selective Cox-2 inhibitors as anti-inflamatory analgesic is becoming more and more common in our environment. We report two cases of tubulointersticial nephritis confirmed by renal biopsy, associated with administration of the two Cox-2 inhibitors currently available on the market, celecoxib and rofecoxib. In both cases, we were talking about elderly women, with deterioration of the general condition and acute renal failure. In the former case, renal biopsy showed an acute tubulo-intersticial nephritis (TIN) so highly "variegated" in its histologic expression. In the second case, was associated with strong indications of chronicity. Treatment with steroid was initiated in both patients and improvement of renal function was observed.

Evidence that addition of azathioprine improves renal function in cyclosporine-treated patients with allograft dysfunction.

Several approaches have been attempted to manage renal allograft dysfunction in cyclosporine-prednisone (CsA-Pred)-treated patients. Conversion to conventional therapy and perioperative triple drug have been associated with high rates of acute rejection episodes, infections, or neoplasms. We report our experience in delayed addition of azathioprine (1-2 mg/kg/day) to CsA/Pred protocol in three groups of patients. Group I (n = 9) had chronic renal function deterioration due to chronic rejection; group II (n = 10) had repeated or severe acute rejection episodes despite adequate CsA levels; and group III (n = 8) had CsA toxicity despite drug tapering. In group I, serum creatinine (SCr) had risen from 2.2 +/- 0.9 to 2.9 +/- 0.7 mg/dl over the 6 months prior to Aza addition (P less than 0.05), renal function declining at a rate of -0.14 +/- 0.12 Cr-1/year. In the 6-month post-Aza, renal function improved at a rate of 0.06 +/- 0.06 Cr-1/year and during the entire follow-up at a rate of 0.04 +/- 0.12 Cr-1/year (P less than 0.05) with stable CsA levels (288 +/- 167 vs. 251 +/- 172 ng/dl, NS). In group II response was worse, though the rate of declining renal function prior to Aza (-0.10 +/- 0.10 Cr-1/year) was almost stopped after Aza. In group III there was very good response to Aza addition, as 7 out of 8 patients improved graft function (baseline SCr 2.5 +/- 0.7 mg/dl vs. 1.9 +/- 0.6 mg/dl at last follow-up, P less than 0.05), with significantly decreased CsA levels (480 +/- 97 vs. 268 +/- 120, P less than 0.05). One patient from group II died from pneumonia, and 6 patients (1 from group I and 5 from group II) lost their grafts. Fifteen patients improved graft function, and 9 worsened after addition of Aza. The bad-responders had significantly higher SCr at baseline compared with the good-responders (3.8 +/- 1.8 vs. 2.7 +/- 0.6 mg/dl, P less than 0.01). Amelioration of chronic graft dysfunction can be achieved by delayed addition of Aza to CsA-Pred in patients with chronic rejection or CsA toxicity. This is accompanied by low rate of acute rejection, good patient and graft survival, and low rate of infections. A worse outcome can be seen in patients with high-baseline SCr levels, suggesting the need for addition of Aza in the initial chronic graft dysfunction.

Expression of adhesion molecules in allograft renal dysfunction. A distinct diagnostic pattern in rejection and cyclosporine nephrotoxicity.

We have studied in thirty renal biopsies (from 30 cadaver allograft patients) the expression of both LFA-1 and VLA-4 leukocyte adhesion receptors and their respective ICAM-1 and VCAM-1 endothelial cell ligands, during early allograft dysfunction (24 +/- 5 days after transplantation), reversed either by antirejection therapy (n = 14) or by reduction in CsA dose (n = 16). We have found that the levels of expression of the integrin VLA-4 and the activation signal AIM/CD69 (activation inducer molecule) on interstitial cells were significantly (P < 0.001) higher in rejection than in nephrotoxicity. A main differential expression pattern was observed for VCAM-1, the endothelial cell ligand of VLA-4. Interestingly, a strong staining pattern of the renal vascular endothelium and 35% of tubular epithelium was obtained with anti-VCAM-1 antibody in rejection, as compared with a weak reactivity in endothelium and discrete staining pattern on tubules in nephrotoxicity. On the other hand, we found that the mean percentage of infiltrating cells bearing LFA-1 molecules and the intensity of ICAM-1 (a LFA-1 ligand) expression on endothelium were closely similar in both rejection and CsA nephrotoxicity. Nevertheless, a discrete significant (P < 0.05) "de novo" expression of ICAM-1 was present on tubular cells during rejection. Our results strongly suggest that in rejection the interstitial cell infiltrate seems to be facilitated by the contribution of both LFA-1/ICAM-1 and VLA-4/VCAM-1 cell adhesion mechanisms, and also that VLA-4/VCAM-1 leukocyte interaction does not play a role in cases with CsA nephrotoxicity. Furthermore, the differential expression patterns of VLA-4 and VCAM-1 molecules found between rejection and CsA nephrotoxicity could provide valuable immunohistochemical criteria in the diagnosis of allograft dysfunction.

Outcome of cadaveric renal transplant patients treated for 10 years with cyclosporine: is chronic allograft nephropathy the major cause of late graft loss?

BACKGROUND: The introduction of cyclosporine (CsA) has improved the short-term outcome of renal transplantation, but its effect on the long-term survival is not well known. METHODS: We analyzed 128 cadaveric first renal transplant recipients with CsA and prednisone as basal immunosuppression followed for at least 10 years, and we have compared them with a group of 185 historical patients treated with azathioprine (Aza) and prednisone. RESULTS: The 1-year graft survival was 83% in the CsA-treated patients and 68% in the Aza-treated patients (P<0.025), and the differences were significant for 3 years. Acute rejection accounted for the 10.9% of losses in CsA-treated patients and for 23.8% of losses in Aza-treated patients (P=0.046). Chronic allograft nephropathy was the cause of graft losses in 40.6% and 16.8% of cases (P=0.008). Patient survival at 5 years was 88% in CsA-treated patients and 79% in the Aza-treated patients (P<0.025). When analyzing the data of the 64 CsA-treated patients and the 84 Aza-treated patients with one functioning graft at 10 years, mean serum creatinine values were significantly higher in the CsA-treated patients at all time points but the increases were not significantly different. At 10 years, mean blood pressure was higher (P=0.002), and hypercholesterolemia (P=0.011) and hyperuricemia (P=0.000) were more prevalent in the CsA-treated patients. CONCLUSIONS: CsA resulted in a better short-time patient and graft survival that was not maintained in the long-term outcome. Chronic allograft nephropathy was the leading cause of graft loss in CsA-treated patients. Graft function was poorer in the CsA-treated patients, but its decline was similar in the two groups.

Delayed graft function does not reduce the survival of renal transplant allografts.

BACKGROUND: The aim of the present study was to investigate the effect of delayed graft function (DGF) in graft outcome when adjusted by the presence of acute rejection in the first month after transplantation. METHODS: A total of 437 cadaveric renal transplant patients on cyclosporine and steroids were included in the study. Variables related to donor, recipient, and graft were prospectively collected. RESULTS: The incidence of DGF was 44.4%. When patients dying with a functioning graft were censored, graft survival rates at 1 and 6 years were similar in patients with immediate function to those with DGF, when rejection was not present (96% and 81% vs. 95% and 83%, respectively). Rejection negatively influenced graft survival rates at 1 and 6 years, both in patients with immediate graft function (80% and 73%, P<0.05 vs. no DGF/no rejection) and more deeply in those with associated DGF (77% and 62%, P<0.001 vs. no DGF/no rejection). Rejection was more frequently diagnosed in patients with DGF than in those with immediate graft function (50% vs. 39.9%, P<0.05). Length of hospitalization was longer and the number of needle core biopsies was higher in patients with DGF or rejection. The presence of both complications had an additive effect. CONCLUSIONS: This study showed that DGF did not adversely affect kidney graft survival in patients without rejection. However, it increased the length of hospitalization and the number of graft biopsies, thus increasing the cost of transplantation. Moreover, rejection was more frequent in patients with DGF, and it had a negative impact on graft outcome. Because the association of DGF and rejection gave the poorest outcome, an effort should be made to prevent both complications.

Retinoids as a potential treatment for experimental puromycin-induced nephrosis.

1 Puromycin aminonucleoside (PAN)-induced nephrosis is a model of human minimal change disease. In rats, PAN induces nephrotic-range proteinuria, renal epithelial cell (podocyte) damage, infiltration of mononuclear leukocytes, and apoptosis of several renal cell types. 2 Retinoic acid (RA) modulates a wide range of biological processes, such as inflammation and apoptosis. Since renal damage by PAN is characterized by inflammatory infiltration and epithelial cell death, the effect of treatment with all-trans RA (tRA) was examined in the PAN nephrosis model and in the cultured differentiated podocyte. 3 Treatment with tRA 4 days after PAN injection did not inhibit the proteinuria peak but reversed it significantly. However, treatment with tRA both before and 2 days after the injection of PAN protected the glomerular epithelial cells, diminishing the cellular edema and diffuseness of the foot process effacement. Preservation of the podocyte architecture correlated with the inhibition of proteinuria. The anti-inflammatory effect of tRA was evidenced by the inhibition of PAN-induced interstitial mononuclear cell infiltration and the decreased renal expression of two molecules involved in monocyte infiltration: fibronectin and monocyte chemoattractant protein-1. TUNEL assays showed that tRA inhibited the PAN-induced apoptosis of cultured differentiated mouse podocytes. 4 We conclude that tRA treatment may prevent proteinuria by protecting the podocytes from injury and diminishing the interstitial mononuclear infiltrate in the model of PAN nephrosis. Retinoids are a potential new treatment for kidney diseases characterized by proteinuria and mononuclear cell infiltration.

Effect of anti-interleukin-1 administration to rats with adriamycin-induced nephrosis.

Rats receiving a single dose of adriamycin (7.5 mg/kg) develop heavy proteinuria and histologic lesions similar to those found in minimal change nephrotic syndrome in humans. We found that whole isolated glomeruli from rats injected with adriamycin secreted an IL-1-like cytokine which closely resembled macrophage IL-1. Maximal IL-1-like activity was detected on day 14 of the experiment when rats were heavily proteinuric. Administration of anti-IL-1 antiserum to rats with adriamycin-induced nephrosis provoked a transient but marked reduction in the urinary protein excretion. Our results indicate that IL-1-could be an important mediator implicated in the development of proteinuria in this experimental nephropathy.

Cicaprost, a prostacyclin analog, protects renal function in uninephrectomized dogs in the absence of changes in blood pressure.

Ten dogs presenting mild chronic renal failure and hypertension after 27 months of uninephrectomy, during which they received a high sodium and high protein diet, were divided in two groups (n = 5) and followed for 15 months. The same diet was maintained and one of the groups received cicaprost treatment. The animals were periodically tested for biochemical and clinical parameters, and at months 0, 3, 6, and 15, glomerular filtration rate and renal plasma flow (RPF) were measured. Renal biopsies were made after 6 months of follow-up. Control group showed a higher thickening of pre- and intraglomerular portions of arteriolar vessels and an enhancement of mesangial matrix when compared with the treated group. Cicaprost also induced a significant elevation in RPF and a significant decrease in filtration fraction. All these findings suggest that cicaprost, an oral stable prostaglandin I2 analog, could have a protective renal effect in this experimental model.

Role of platelet-activating factor in adriamycin-induced nephropathy in rats.

The effect of steroids, heparin and specific PAF-acether antagonists (BN 52021 and triazolobenzodiazepines) on proteinuria and renal histological changes induced in rats by adriamycin was studied. Adriamycin evoked a marked proteinuria that was unaffected by methylprednisolone and slightly reduced by heparin. In contrast, adriamycin-injected rats treated with PAF-acether antagonists had a low proteinuria, if any, and no ultrastructural glomerular alterations. These data suggest that PAF-acether could play a major role in the occurrence of proteinuria and that PAF-acether antagonists might provide a new therapeutic approach in certain human nephropathies.

Tubulointerstitial nephritis and asymptomatic uveitis.

We describe a case of a 10 year-old boy who had fever, weakness, anorexia, weight loss and general malaise. No other remarkable symptoms were present. He had been treated with Aspirin and Ibuprofen. Deterioration of renal function, glucosuria, proteinuria, anemia and increased erythrocyte sedimentation rate were detected. After 7 days observation with no treatment, renal function worsened, glucosuria increased and fever persisted. A renal biopsy was performed and acute tubulointerstitial nephritis was diagnosed. The most common aetiologies of this entity were excluded. An ophthalmologic study revealed bilateral anterior uveitis, therefore the patient was diagnosed as having tubulointerstitial nephritis with uveitis. The child improved on corticosteroid therapy, but uveitis relapsed when treatment was stopped.

Mesangial deposits of IgM in patients with the nephrotic syndrome.

Kidney biopsies from fourteen patients with the nephrotic syndrome were studied by light, immunofluorescence and electron microscopy. Morphologically, all cases showed moderate diffuse mesangial cell proliferation. In all cases, immunofluorescent microscopy demonstrated diffuse and generalized deposits of IgM as the sole or predominant immunoglobulin. Electron microscopic examination showed electron dense deposits localized in the mesangium in seven cases. One nephrotic patient experienced spontaneous remission and eight others were steroid responsive. Only one of the five steroid resistant patients treated with chlorambucil showed clinical remission. Five steroid responsive patients relapsed. At present, four patients are healthy, having not relapsed for the past two years. Although deposits of IgM may be related to the renal pathology in cases of the nephrotic syndrome, immunofluorescence findings do not seem to be sufficiently consistent or characteristic to justify a possible subclassification of the idiopathic nephrotic syndrome.

Mesangial proliferative glomerulonephritis with unusual intramembranous granular dense deposits.

We have studied two patients with histories of upper respiratory tract infection. Hematuria and proteinuria were the presenting renal symptoms in one patients and an acute nephritic syndrome in the other. Serological findings disclosed depression of total hemolytic complement activity with low levels of C3 and the presence of C3Nef activity. Light microscopy showed diffuse mesangial cell proliferation. By immunofluorescence, diffuse deposits of C3 were found in the glomeruli. Ultrastructural studies revealed segmental thickening of the glomerular basement membrane due to the deposition of granular electron-dense deposits in a laminar pattern. We suggest that our cases may represent a variant of hypocomplementemic glomerulonephritis or perhaps the early stages of dense deposit disease.

Spanish experience with cyclosporine.

Our experience with cyclosporine (CsA) in de novo renal transplantation (RT) may be systematized in four consecutive periods. From February 1986 to December 1989, patient survival was higher among 128 consecutive CsA-prednisone-treated cadaver allograft recipients than in previous patients on azathioprine. One-year graft survival was significantly higher in CsA patients, a difference that was thereafter progressively reduced: at 10 years graft survivals were 50% versus 45%, and at 15 years 37% versus 35%, respectively. The most frequent cause of graft loss was death with a functioning graft. Acute rejection caused more graft losses among Aza-treated patients than CsA-treated ones. However, chronic allograft nephropathy produced more graft losses in CsA patients. After this initial experience with CsA-based immunosuppression we developed a second phase in which better results were obtained in 209 first cadaveric RT recipients. The use of lower initial CsA doses, more rapid steroid tapering, and a better approach to CsA nephrotoxicity or chronic nephropathy by substantial reductions in CsA exposure and delayed azathioprine addition, lead to these improvements. From March 1995 through 2000, we used the new microemulsion CsA formulation (Neoral) with steroids or azathioprine in 110 first de novo RT recipients. Mean donor and recipient ages were significantly higher in this phase than in previous ones; consequently, survival and function results were slightly worse. Blood CsA concentrations measured 2 hours after administration represent a more precise predictor of exposure than trough concentrations. The last step in optimizing Neoral use in RT on our service was application of reduced-dosage with C2 monitoring instead of classical C0 testing. Acute rejection and treatment failure rates were low and renal allograft function improved with respect to previous full-dose C0 experiences. CsA use has evolved in these two decades in four consecutive phases. Short-term results have improved or been maintained from phase to phase, even with expanded-criteria donors until excellent features during last years with C2 monitoring and combination with potent drugs such as MMF or everolimus. During the coming years, new drugs and protocols will allow even more optimized use.

Evidence suggesting a role for platelet-activating factor (PAF) in experimental nephrotic syndrome.

Sprague-Dawley rats injected with a single dose of adriamycin at 7.5 mg/kg/day developed an important and persistent proteinuria from day 14. Animals treated from day 0 to 3 weeks with PAF-receptor antagonists (BN 52021 or alprazolam) did not present (p less than 0.0005) the adriamycin-induced proteinuria or only to a very low extent. Furthermore, epithelial glomerular cells presented in these animals a normal aspect, while in rats injected with adriamycin, but not treated, the epithelial cells showed effacement of foot processes and intensive degenerative changes. By contrast, rats treated with steroids or cyclosporin did not present a significant reduction in proteinuria or improvements in epithelial cell lesions. Rats injected with adriamycin also presented an increase in the number of inflammatory infiltrating cells, chiefly la(+)-reactive cells (OX6+ cells), macrophages (ED1+ cells) and T-cytotoxic/suppressor cells (OX8+ cells). Concomitant administration of PAF-receptor antagonists induced a significant reduction in the number of these cells. Glomerular cells from normal control rats incubated with adriamycin incorporated 3H-acetate into a polar lipid with biological and migratory characteristics on thin-layer chromatography similar to synthetic PAF. On the whole, our data suggest a role for PAF in the pathogenesis of experimental nephrotic syndrome induced by adriamycin.

[Acute interstitial nephritis caused by clozapine]. / Nefritis intersticial aguda inducida por clozapina.

We are reporting a case of a 69 years old man developed acute renal failure due to interstitial nephritis during treatment with the drug clozapine, and that improve after to discontinuation of this drug. The clozapine is a new antipsychotic drug that may produce severes adverses reactions, like medullary toxicity. Recently 10 cases of clozapine-induced AIN have been reported. We want to associate to the cases publicated with a new case because it is a severe adverse reaction.

[Minimal-change disease with mesangial IgA deposits associated with Sjogren syndrome]. / Enfermedad de cambios mínimos con depósitos mesangiales de IgA asociada a síndrome de Sjögren.

Sjögren's syndrome may be accompanied by a dysregulation of IgA system implying the presence of increased serum polymeric IgA or circulating immune complexes and their consequent deposition within the kidney. In this context IgA nephropathy may only represent one of the complications brought by IgA deposition. Glomerular involvement and primary Sjögren's syndrome has been described previously only in isolated case reports, membranous nephropathy and membranoproliferative glomerulonephritis have been reported. We have not found any case of minimal change disease and glomerular IgA deposition associated with Sjögren's syndrome. In this patient nephrotic syndrome was related to serum increase of CA 19-9; this association has been reported in only three previous cases.

[Antiphospholipid antibodies in systemic lupus erythematosus: incidence, significance and relation to lupus nephritis]. / Anticuerpos antifosfolípidos en el lupus eritematoso sistémico: incidencia, significación y relación con la nefritis lúpica.

The prevalence of three different types of antiphospholipid antibody in 88 consecutive patients with systemic lupus were 27.2% for lupus anticoagulant (LAC), 31.8% for anticardiolipin antibody (aCL), and 13.6% for falsely positive serologic tests for syphilis (FPSTS). The three tests were correlated, thus confirming the overlapping specificities of this family of antibodies. Although FPSTS was not associated with any particular manifestation of systemic lupus, aCL correlated with thrombosis (p = 0.0001), thrombopenia (p = 0.009), neuropsychiatric features (p = 0.02) and membranous nephropathy (p = 0.001), while LAC correlated with thrombosis (p = 0.001) and hemolytic anemia (p = 0.04). The previously unreported association between membranous nephropathy and aCL might explain some features of the former, particularly the higher incidence of thromboembolic complications and the poorly known relation with renal vein thrombosis.