Mechanisms underlying sCD40 production in hemodialysis patients.

CD40 and its ligand (CD40L) regulate several cellular functions, including T and B-cell activation. The soluble form of CD40 (sCD40) antagonizes CD40/CD40L interaction. Patients undergoing hemodialysis (HD) present elevated sCD40 serum levels, which underlying molecular mechanisms are unknown. We studied sCD40 serum and urinary levels, CD40 membrane and gene expression and membrane shedding in HD, uremic not-HD patients (UR) and healthy subjects (N). We found that in HD sCD40 serum levels were higher than UR and N, being significantly elevated in anuric patients, and that sCD40 correlated to renal function in UR subjects, who presented also a reduced sCD40 urinary excretion rate. HD and UR presented reduced CD40 membrane and gene expression. The concentration of TNF-α converting enzyme (TACE), responsible for CD40 cleavage was not different between HD and N. Therefore the reduced renal clearance is the main cause of elevated sCD40 levels in HD. This finding could have relevant clinical implications.

Pretransplant and protocol biopsies may help in defining short and mid-term kidney transplant outcome.

Although many variables may affect long-term graft survival no biomarker is available to identify donor kidney with poor quality and with inadequate short and long-term outcome. While in marginal donors pre-transplant renal biopsies are commonly performed to establish if donor kidneys are suitable for transplantation they are not performed in standard donors. In this study we assessed the relevance of pre-transplant morphological features on post-transplant renal function and evaluated the association between perioperative parameters with posttransplant histological and clinical findings. Kidney transplant recipients undergone pre-transplant and post transplant protocol biopsies at 1, 6, and 12 months were enrolled in the study. Perioperative and posttransplant clinical and biochemical parameters were recorded. Semiquantitative analysis of PAS stained kidney sections was used to determine the degree of lesions. Glomerular volume was measured by computed morphometry. A strong inverse correlation was found between donor age and renal graft function at 1, 6, and 12 months after transplantation. A prompt functional recovery was associated with a better renal function at 6 months and one year. Kidneys with higher glomerular volume demonstrated a lower serum creatinine at 1 month. Higher tubulo-interstitial grading at protocol biopsies was associated with a poor renal function at 1 month. Our findings confirm the importance of donor age in kidney transplant long-term outcome and demonstrate that pretransplant and protocol biopsies are valid options to determine graft outcome and to define therapeutic strategies and tailor immunosuppressive regimen for each patient.

Erythema nodosum in kidney transplant recipient: a rare complication of pneumonia treatment.

Erythema nodosum (EN) is a cutaneous inflammatory reaction, usually reported in young women, but it is rarely observed among transplant patients. Localization in the lower extremities is typical, mostly involving the anterior surfaces of the legs. Several viral, bacterial, mycotic, and non-infectious etiologies, such as autommune disorders, drugs, inflammatory bowel diseases, sarcoidosis, pregnancy, and malignancies, have been found. We describe the case of a young woman kidney transplant recipient developing bilateral, erythematous, warm nodules localized on the anterior surface of her legs after antibiotic treatment for pneumonia with levofloxacin. Her immunosuppression was sirolimus and mycophenolate mofetil. EN was diagnosed by skin biopsy; microscopic examination showed septal panniculitis with granulomas. As a complete remission of the lesions was obtained in our patient after interruption of levofloxacin therapy, we suspect that levofloxacin was involved in the pathogenesis of EN. In fact, the management of EN is based on the treatment of underlying or associated conditions.

Robotic-assisted laparoscopic donor nephrectomy with transvaginal extraction of the kidney.

Transvaginal recovery of the kidney has recently been reported, in a donor who had previously undergone a hysterectomy, as a less-invasive approach to perform laparoscopic live-donor nephrectomy. Also, robotic-assisted laparoscopic kidney donation was suggested to enhance the surgeon's skills during renal dissection and to facilitate, in a different setting, the closure of the vaginal wall after a colpotomy. We report here the technique used for the first case of robotic-assisted laparoscopic live-donor nephrectomy with transvaginal extraction of the graft in a patient with the uterus in place. The procedure was carried out by a multidisciplinary team, including a gynecologist. Total operative time was 215 min with a robotic time of 95 min. Warm ischemia time was 3 min and 15 s. The kidney was pre-entrapped in a bag and extracted transvaginally. There was no intra- or postoperative complication. No infection was seen in the donor or in the recipient. The donor did not require postoperative analgesia and was discharged from the hospital 24 h after surgery. Our initial experience with the combination of robotic surgery and transvaginal extraction of the donated kidney appears to open a new opportunity to further minimize the trauma to selected donors.

Mesenchymal stem cells infusion prevents acute cellular rejection in rat kidney transplantation.

Mesenchymal stem cells (MSC) are multipotent cells that differentiate into various mature cell lineages. MSC show immunomodulatory effects by inhibiting T-cell proliferation. We evaluated the effect of the infusion of MSC in rats experimental kidney transplantation. Sprague-Dawley transgenic rats (SD) able to express the green fluorescent protein (EGFP) were used as MSC donors. Syngeneic (Lewis to Lewis, n = 10) and allogeneic (Fischer to Lewis, n = 10) kidney transplantations were performed after bilateral nephrectomy. Five transplanted rats who received syngeneic grafts, were treated with 3 x 10(6) MSC (Gr B), while the other 5 did not received MSC (Gr A). Five rats with allogenic grafts received 3 x 10(6) MSC (Gr C) and another 5 did not receive MSC (Gr D). The MSC were infused directly into the renal artery of the graft. No immunosuppressive therapy was provided. The animals were killed after 7 days. Biochemical analysis for renal function, histological (Banff criteria) and immunohistological analysis (ED1+ and CD8+) were performed on treated animals. MSC improved kidney function in Gr B and D vs Gr A and C. The tubular damage appeared to be less severe among Gr B and Gr D with respect to Gr A and C (P < .01). Vasculitis was more accentuated in Gr A and C (P < .01). MSCs reduced the inflammatory infiltrate; in Gr B and D, the number of ED1+ cells was lower than in Gr A and C (P < .005), which was also observed for CD8+ cells (P < .05). Our study demonstrated that the infusion of MSC attenuated histological damage from acute rejection by reducing the cellular infiltration.

Which is the most suitable and effective route of administration for mesenchymal stem cell-based immunomodulation therapy in experimental kidney transplantation: endovenous or arterial?

Immunomodulating cell therapy represents a new perspective for the control of cellular immune responses that determine the occurrence of acute rejection (ACR) in allo-transplantation. Mesenchymal stem cells (MSC) demonstrate immunoregulatory effects by inactivating T-cell components that regulate tissue damage in transplantation models. The presumed mechanism of action is recruitment of cells by a cytokine network. The purpose of this study was to test which route of administration (intra-arterial vs intravenous) was the most effective route to achieve immunomodulating effects in experimental rat kidney transplantation. Transgenic Sprague-Dawley rats (SD) expressing the enhanced green fluorescent protein (EGFP) at the somatic level were used as MSC donors: Allogeneic Fischer to Lewis grafts (n = 4 per group) were performed in rats after bilateral nephrectomy. In Gr B, 3 x 10(6) MSCs were infused into the renal graft artery, whereas in Gr C, they were infused into the tail vein. The untreated Gr A were a control group. No immunosuppressive therapy was administered. The animals were sacrificed at day 7 postoperatively. Biochemical analysis for renal function, histological (Banff criteria) and immunohistological (anti-EGFP-Immunoglobulin) analysis were performed on the transplanted animals. In Gr B, functional recovery was more rapid (creatinine: Gr B vs Gr C, P < .05). The inflammatory infiltrate in the graft was less in Gr B vs Gr C, with preservation of tubules, arteries, and glomeruli (P < .01). Intra-arterial infusion of MSCs was more effective to control ACR.

Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy.

We investigated Toll-like receptors (TLR-3, -4 and -7) expression in circulating mononuclear cells of patients with immunoglobulin A nephropathy (IgAN), a disease with debated relationships with mucosal immunity. TLR-4 expression (detected by fluorescence activated cell sorter) and mRNA transcriptional levels (Taqman) were significantly higher in patients with IgAN than in healthy controls (P = 0.00200 and P = 0.0200). TLR-3 and TLR-7 were not modified significantly. In IgAN patients proteinuria was correlated significantly with TLR-4 expression (P = 0.0312). In a group of nephrotic syndromes, TLR-3, -4 and -7 expression was similar to healthy controls. A significant difference in TLR-4 expression and mRNA levels was found between very active IgAN patients (proteinuria > 1 g/1.73 m(2)/day in association with severe microscopic haematuria) and inactive patients (proteinuria < 0.5 g/1.73 m(2)/day, with absent or minimal haematuria). No correlation with levels of aberrantly glycosylated IgA1, age, renal biopsy features or therapy was found. This study shows for the first time an up-regulation of TLR-4 in circulating mononuclear cells of patients with IgAN, particularly in association with proteinuria and heavy microscopic haematuria.

The improvement of ischemia/reperfusion injury by erythropoetin is not mediated through bone marrow cell recruitment in rats.

BACKGROUND: Ischemia/reperfusion (I/R) injury is a major cause of acute renal failure in kidney transplantation; however, the mechanisms of kidney damage and repair are not yet clear. So far no treatment has been effective to prevent I/R injury. In the present study we evaluated the effect of erythropoetin (EPO) in I/R injury in rats. We investigated the role of bone marrow cells (BMC) in kidney repair and the effect of EPO on BMC recruitment. MATERIALS AND METHODS: Female Sprague Dawley rats transplanted with male BMCs underwent I/R injury. In the treatment group rats received 5000 IU of EPO 30 minutes before renal ischemia. At 2 and 4 weeks after I/R, rats were humanely killed and we measured creatinine clearance (glomerular filtration rate [GFR]), proteinuria, and body weight (BW). Renal tissue was harvested for histologic and molecular analysis. Fluorescein in situ hybridization (FISH) and TUNEL were used to determined the presence of male cell chimerism and apoptosis in renal tissue. RESULTS: At 4 weeks after I/R, EPO significantly improved GFR (1.8 +/- 0.2 vs 1.2 +/- 0.14 mL/min; P < .05). No significant differences between EPO and control rats were observed in proteinuria, BW, and hemoglobin levels at 2 and 4 weeks. After death, the kidney showed only minimal tubulointerstitial changes, which were more marked in control rats. FISH analysis demonstrated a low degree of microchimerism, not significantly different between EPO and control rats. Apoptosis decreased between 2 and 4 weeks after I/R, in both EPO and control groups. CONCLUSION: EPO improved GFR and injury at 4 weeks after I/R; however, it did not enhance the recruitment of BMC.

Rapamycin reduces proteinuria and renal damage in the rat remnant kidney model.

Rapamycin is an immunosuppressive drug used to prevent acute allograft rejection in solid organ transplantation. It shows less nephrotoxicity than calcineurin inhibitors. We evaluated the effect of rapamycin in rats undergoing 5/6 nephrectomy, a model of proteinuric and progressive renal failure. Fourteen days after surgery rats were randomized either to receive rapamycin or to remain untreated (control). Rats were humanely killed on day 91; serum creatinine, creatinine clearance, and proteinuria were assessed. Renal sections were stained with periodic acid-Schiff to evaluate glomerular volume (Gv), glomerulosclerosis (GS) and tubulointerstitial damage (TIS); we evaluated GS and TIS by Sirius red staining (SR). Epithelial-to-mesenchymal transition (EMT) was assessed by immunohistochemistry. Rapamycin affected neither serum creatinine nor creatinine clearance; it reduced Gv (controls, 5.9 +/- 3.1 x 10(6); rapamycin, 1.3 +/- 0.7 x 10(6) microm(3)) and proteinuria (control, 349 +/- 146; rapamycin, 56 +/- 27 mg/24 h; P < .05); rapamycin ameliorated GS (control, 78 +/- 7; rapamycin, 36 +/- 7%; P < .05; SR: control, 13.2 +/- 3.5; rapamycin, 3.8 +/- 1.0%; P < .05), and TIS (control, 3.25 +/- 0.5; rapamycin, 1.0 +/- 0.1; P < .05; SR: control, 29 +/- 3; rapamycin, 11 +/- 3%; P < .05). Rapamycin reduced alphaSMA (control, 3.25 +/- 0.5; rapamycin, 1.0 +/- 0.1; P < .05), VIM (control, 3.5 +/- 0.6; rapamycin, 1.0 +/- 1.4; P < .05), and CD68(+) cells infiltration (control, 110 +/- 43; rapamycin, 24 +/- 1 cells; P < .05). Rapamycin slows the progression of renal damage in the rat remnant kidney and may represent a novel approach to the treatment of chronic kidney disease.

[Hepatocyte growth factor and kidney]. / Hepatocyte Growth Factor (HGF): ruolo nella embriogenesi e nella fibrosi renale.

HGF is a multifunctional polypeptide with mitogenic, motogenic and morphogenic effects. These effects are mediated by c-met, a specific receptor of HGF and a member of the receptor tyrosine kinase superfamily, virtually expressed in every type of kidney cell. HGF has a central role during embryogenesis since it stimulates epithelial differentiation of metanephric mesenchymal cells and induces branching tubules, as experiments in epithelial cells cultures demonstrated. Several studies have shown also that HGF accelerates the recovery from toxic-ischemic acute renal failure. This effect seems to be mediated by the inhibition of programmed cell death and an increased cell survival. HGF inhibits apoptosis by upregulating the protooncogene Bcl-2 and downregulating Bax. Since HGF can modulate extracellular matrix turnover, authors suggest its beneficial role in tissue remodelling and particularly in chronic renal diseases. Several studies reported a key role for HGF in reducing interstitial fibrosis and glomerular sclerosis, both in in vivo and in vitro models. This protective effect is secondary to HGF antagonizing the profibrotic action of TGF-beta. HGF modulates the balance between synthesis and degradation of extracellular matrix, increasing the expression of metalloproteases and reducing the production of their specific inhibitors TIMPs. Furthermore HGF suppresses the effect of TGF-beta by blocking the axis TGF-beta/Smad. Last, the antifibrotic effect of HGF might be modulated by the proliferative status of target cells. To sum up, the supplementation of exogenous HGF or the induction of endogenous HGF expression may provide an effective therapeutic strategy for combating chronic renal diseases.

A randomized trial of steroid avoidance in renal transplant patients treated with everolimus and cyclosporine.

In this randomized trial renal transplant recipients were treated with basiliximab, everolimus 3 mg/day, low-dose CsA. At transplantation, patients were randomized to stop steroids at the seventh day (group A) or to continue oral steroids in low doses (group B). Of the 113 patients enrolled, 65 were randomized to group A and 68 to group B. All patients were followed for 2 years. During the study 28 (43%) group A patients required reintroduced corticosteroids. One patient died, in group B. The Graft survival rate was 97% in group A and 90% in group B. There were more biopsy-proven rejections in group A (32% vs 16%; P = .044). The mean creatinine clearance was 54 +/- 21 mL/min in group A vs 56 +/- 22 mL/min in group B. Mean levels of serum cholesterol tended to be lower in group A, but the difference was of borderline significance (191 +/- 91 vs 251 +/- 188 mg/dL; P = .07). Vascular thrombosis (0 vs 5) and pneumonia requiring hospitalization (2 vs 7) tended to be more frequent in group B. Only three cases of CMV infection (1 vs 2) occurred. An immunosuppressive therapy with everolimus and low-dose CsA allows one to obtain excellent renal graft survival and stable graft function at 2 years. Early interruption of steroids in patients treated with this regimen may increase the risk of acute rejection, but neither affects graft survival nor graft function, while possibly reducing the risk of hyperlipemia and vascular thrombosis. About 60% of patients given everolimus and low-dose CsA can definitively stop steroids after 1 week.

Platelet-Independent defect in hemostasis associated with sirolimus use.

Sirolimus is currently used to prevent rejection of solid organ transplant, and sirolimus-eluting stents have shown promise for the prevention of coronary artery restenosis. Thrombocytopenia is a well-known adverse effect of sirolimus limiting its use. Herein we report on a patient in whom sirolimus caused a platelet-independent hemostasis defect. The patient was a 52-year-old woman who underwent renal transplant with consequent normal kidney function. The immunosuppressive regimen included basiliximab, steroids, and cyclosporine induction later shifted to sirolimus and mycophenolate due to biopsy findings of tubular necrosis on day 6 posttransplantation. At discharge the serum creatinine was 0.7 mg/dL. Four months after transplantation the patient was admitted to our hospital because of fever (37.5 degrees C to 38 degrees C), anorexia, and asthenia. Blood analysis showed: creatinine 1.7 mg/dL, Hb 9.6 g/dL, WBC 6 x 10(3)/microL, PLT 123 x 10(3)/microL, liver function tests normal, LDH 720 mU/mL, fibrinogen 628 mg/dL, d-dimer 0.42 ng/mL, FDP > 40 ng/mL, INR 1.10, PT 87%, aPTT 40 seconds. Cultures and tests for infection were negative. Serum sirolimus level was 25.9 ng/mL. The following day the serum creatinine rose to 2.3 mg/dL and diuresis fell to 20 mL/h. Multiple bleeding times (Ivy test) performed before the renal biopsy were repeatedly over 30 minutes (normal 3 to 5 minutes), despite normal platelet count and platelet function studies. There was no spontaneous aggregation and in vitro aggregation was normal (collagen, ADP, adrenalin, and ristocetin induced). Coagulation studies showed a defect in fibrin formation and a reduction of fibrinolysis. Suspension of sirolimus treatment was followed by remission of fever, improvement of renal function (serum creatinine 1.2 mg/dL), and normalization of bleeding time.

[Hepatocyte growth factor (HGF) reduces the expression of profibrotic factors in human isolated glomeruli]. / Hepatocyte growth factor (HGF) riduce l'espressione di fattori profibrotici in glomeruli umani isolati.

BACKGROUND: The imbalance between the synthesis and degradation of the mesangial matrix causes glomerulosclerosis and ultimately leads to chronic renal failure. HGF is a pleiotropic cytokine involved in angiogenesis, morphogenesis, organogenesis, and bone remodeling. Recently, we and other investigators have shown that HGF has a central role in the recovery of acute renal failure. Furthermore, HGF treatment halts the progression of kidney disease in a murine model of chronic renal failure. The aim of the present study was to evaluate the effect of HGF on the mRNA levels of molecules involved in the extracellular matrix turnover and of the c-met receptor in isolated human glomeruli. METHODS: Human glomeruli were isolated by microdissection from donor kidney biopsies just before transplantation. Glomeruli were extensively washed and incubated with culture media containing HGF (50 ng/mL) for 24 h at 37 C. Glomeruli incubated without HGF were used as controls. After 24 h, glomeruli were washed and freezed and thawed three times. The expression of c-met, (alpha2) IV collagen, TGF-beta, metalloproteases 9 (MMP9), and of the inhibitor of metalloproteases-1, TIMP-1 was evaluated by in situ reverse transcription (RT) and polymerase chain reaction (PCR). beta-actin was used as a housekeeping gene. RESULTS: The (alpha2)IV collagen mRNA level was decreased by HGF in human glomeruli. TGF-beta and TIMP-1 gene expression was markedly reduced by HGF treatment, whereas the expression of MMP-9 and c-met did not change. Under light-microscopic examination, kidney biopsies showed neither glomerular hypercellularity nor mesangial expansion. CONCLUSIONS: HGF treatment reduces the expression of extracellular matrix components and of profibrotic factors in human glomeruli. Our results confirm a protective role of HGF in glomerulosclerosis.

Hepatocyte growth factor/scatter factor released during peritonitis is active on mesothelial cells.

Peritonitis causes mesothelial detachment that may result in persistent peritoneal denudation and fibrosis. We investigated whether hepatocyte growth factor (HGF), a scatter factor that induces detachment from substrate and fibroblastic transformation of several cell types, is produced during peritonitis and is active on mesothelial cells. We studied 18 patients on peritoneal dialysis, 9 uncomplicated, 9 with peritonitis. HGF was measured in serum, peritoneal fluid, and supernatant of peripheral blood mononuclear cells and peritoneal mononuclear cells. Primary culture of human peritoneal mesothelial cells and the human mesothelial cell line MeT-5A were conditioned with recombinant HGF, serum, and peritoneal fluid. HGF levels were significantly higher in serum and peritoneal fluid of peritonitic than uncomplicated patients. Mononuclear cells of peritonitic patients produced more HGF than cells of uncomplicated patients. Recombinant HGF, serum, and peritoneal fluid of peritonitic patients caused mesothelial cell growth, detachment, transformation from epithelial to fibroblast-like shape, overexpression of vimentin, and synthesis of type I and III collagen. In conclusion, HGF released during peritonitis causes a change in mesothelial cell phenotype and function. HGF may affect the healing process facilitating repair through mesothelial cell growth, but may contribute to peritoneal fibrosis inducing cell detachment with mesothelial denudation and collagen synthesis.

Cyclosporine induces different responses in human epithelial, endothelial and fibroblast cell cultures.

BACKGROUND: Nephrotoxicity, accelerated atherosclerosis, and graft vascular disease are common complications of cyclosporine long-term treatment characterized by a wide disruption of organ architecture with increased interstitial areas and accumulation of extracellular matrix (ECM). How cyclosporine induces these changes is not clear, but it is conceivable that they are the sum of changes induced at the cell level. METHODS: We studied the effects of cyclosporine on human endothelial (HEC), epithelial (HK-2), and fibroblast (MRC5) cells. Cell proliferation was evaluated by cell counting, apoptosis and collagen production by enzyme-linked immunosorbent assay, and nitric oxide by measuring the concentration of nitrite/nitrate in the cell supernatant. (alpha1)I and (alpha2)IV collagen, matrix metalloprotease-9 (MMP9), and tissue inhibitors of metalloprotease-1 (TIMP-1) mRNA levels were measured by reverse transcription-polymerase chain reaction. Proteolytic activity was evaluated by zymography. RESULTS: Cyclosporine showed a marked antiproliferative and proapoptotic effect on endothelial and epithelial cells. Fibroblast growth was not affected by cyclosporine. Nitric oxide was up-regulated by cyclosporine in epithelial cells and fibroblasts but not in endothelial cells. (alpha1)I and (alpha2)IV collagen synthesis was increased in cyclosporine-treated endothelial and epithelial cells, respectively. Proteolytic activity was increased in endothelial and epithelial cells. TIMP-1 mRNA was up-regulated by cyclosporine in fibroblasts. CONCLUSIONS: Our results demonstrate that cyclosporine exhibits an antiproliferative effect on endothelial and epithelial cells. This effect is associated with induction of apoptosis probably via nitric oxide up-regulation in epithelial cell cultures. Cyclosporine treatment induces ECM accumulation by increasing collagen synthesis in endothelial and epithelial cells and reducing its degradation by up-regulating TIMP-1 expression in fibroblasts. We conclude that cyclosporine affects cell types differently and that the disruption of organ architecture is the result of multiple effects at the cell level.

Hemodialysis prevents liver disease caused by hepatitis C virus: role of hepatocyte growth factor.

UNLABELLED: Hemodialysis prevents liver disease caused by hepatitis C virus: Role of hepatocyte growth factor. BACKGROUND: Hemodialysis increases markedly the serum levels of hepatocyte growth factor (HGF) so that regular dialysis treatment (RDT) mimics the regular administration of HGF as a drug. Therefore, we have studied the effects of dialysis-associated HGF production on the severity of liver damage caused by hepatitis C virus (HCV). METHODS: Biochemical tests of liver function and liver biopsy were performed in 10 patients on RDT and in 11 patients without renal disease (WRD) converted to anti-HCV serum-positive test for the same time (48 +/- 4 months). The HGF serum concentration was measured by enzyme immunoassay. In patients on RDT, HGF was measured just before starting a dialysis session (T0), at 15 and 240 minutes of dialysis (T15 and T240), and 24 hours later (T24 hr). RESULTS: Serum HGF was similar in WRD (average 0.17 ng/ml) as in RDT at T0 (0.25 ng/ml). In RDT serum HGF increased markedly at T15 and T240 (5.51 and 2.67 ng/ml, respectively, P < 0. 001 vs. WRD and T0) and was still higher than baseline at T24 hr (0. 41 ng/ml, P < 0.05). Both grade of necroinflammatory activity and stage of fibrosis were significantly lower in RDT than in WRD (both, P < 0.001). The number of apoptotic hepatocytes was also significantly reduced in patients on RDT compared with patients WRD. CONCLUSION: These results show that HCV-related liver disease is more benign in patients on RDT. The phenomenon may depend on the marked and prolonged HGF release caused by dialysis.

Henoch-Schönlein purpura in a chronic hemodialysis patient.

We describe a patient on maintenance hemodialysis who developed purpura, abdominal pain with bloody stool, and gross hematuria. A skin biopsy revealed leukocytoclastic vasculitis with IgA deposits. This is the first report of Henoch-Schönlein purpura in a hemodialysis patient.