Renal disease in sarcoidosis patients in a German multicentric retrospective cohort study.

INTRODUCTION: Sarcoidosis is a systemic granulomatous disease potentially affecting every organ system. Renal involvement is reportedly rare, and the evidence consists of case reports and cohort studies. Systematic investigations are scarce and show a varying prevalence ranging from <1% to 30-50%. METHODS: We retrospectively analyzed data from patients with a recent diagnosis of sarcoidosis from five tertiary care centers focusing on renal sarcoidosis. RESULTS: We analyzed data from 327 patients with sarcoidosis between 2001 and 2021. Of 327 patients, 109 (33.3%) had probable or definite renal sarcoidosis. 90 (27.5%) had histopathologic confirmation. 57 (64%) had an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The most prominent associated finding was an elevated soluble interleukin-2 receptor. Patients with renal sarcoidosis more frequently received glucocorticoids than other non-renal sarcoidosis patients (92% vs. 78%, p < 0.01). Also, azathioprine (38% vs. 16%, p < 0.001) and mycophenolate mofetil (5% vs. 1%, p < 0.05) were more frequently used in renal sarcoidosis compared to non-renal sarcoidosis, whereas methotrexate was used less frequently (7% vs. 17%, p < 0.05). CONCLUSIONS: Our data of the largest cohort with biopsy-confirmed renal sarcoidosis demonstrate a higher prevalence (27.5% of all patients) than previously published with a relevant disease burden. The urinary findings in most cases were only mildly abnormal, and some patients did not have renal biopsy despite abnormal urinary results. A renal workup should be performed in all patients with a new diagnosis of sarcoidosis.

Safety and efficacy of secukinumab in patients with giant cell arteritis (TitAIN): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis. METHODS: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion. Participants were assigned (1:1) to receive 300 mg secukinumab or placebo subcutaneously once a week up to week 4 and every 4 weeks thereafter. In both treatment groups, prednisolone dose was tapered down to 0 mg over a 26-week period. Patients, investigator staff, and clinical trial team were masked to the treatment assignment. The primary endpoint was the median proportion (Bayesian analysis) of patients with sustained remission until week 28 in the full analysis set (ie, all patients who received at least one dose of assigned treatment, analysed according to treatment assigned at randomisation). Sustained remission rate of the placebo group from a previous trial of tocilizumab in patients with giant cell arteritis was used to derive the prior distribution of placebo sustained remission rate for the primary endpoint. The safety of secukinumab was assessed in the safety set (ie, all patients who received at least one dose of study treatment, analysed according to study treatment received). This trial is completed and is registered with ClinicalTrials.gov, NCT03765788. FINDINGS: Of the 65 patients who were assessed for eligibility, 52 patients (median age 75 years [IQR 69-79]; 35 [67%] female and 17 [33%] male, 52 [100%] White) were enrolled between Jan 30, 2019 and March 30, 2020 and were randomly assigned to receive secukinumab (n=27) or placebo (n=25). Four of 27 patients in the secukinumab group and eight of 25 patients in the placebo group discontinued treatment by week 28 of the study. On the basis of the Bayesian analysis, the median proportion of patients in sustained remission until week 28 was 70% (95% credibility interval 52-85) in the secukinumab group versus 20% (12-30) in the placebo group. The incidence of adverse events was similar in the secukinumab (27 [100%] of 27 patients had any adverse event) and placebo groups (24 [96%] of 25 patients had any adverse event); the most common adverse events were hypertension (six [22%] of 27 patients in the secukinumab group and eight [32%] of 25 patients in the placebo group) and nasopharyngitis (five [19%] of 27 patients in the secukinumab group and five [20%] of 25 patients in the placebo group). Two patients (one in each group) died during the study, neither of which was considered to be related to study treatment. INTERPRETATION: Patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, in combination with glucocorticoid taper regimen. Secukinumab was tolerated well with no new safety concerns. This proof-of-concept phase 2 study further supports the development of secukinumab as a treatment option for people with giant cell arteritis. FUNDING: Novartis Pharma.

[Nephrological management and drug dosing in patients with rheumatic diseases and renal insufficiency]. / Nephrologisches Management und Medikamentendosierung bei Rheumapatienten mit Niereninsuffizienz.

BACKGROUND: In patients with inflammatory rheumatic diseases and renal insufficiency there are two challenges for physicians: to adapt the antirheumatic medication to the renal function and to carry out a nephroprotective treatment that prevents long-term deterioration of renal function and reduces the elevated cardiovascular risk. METHODS: A literature search (in PubMed) was carried out and the current state of knowledge on nephroprotective treatment strategies and the treatment of rheumatic diseases in the presence of renal insufficiency was collated, evaluated and summarized. RESULTS: Lifestyle interventions, especially the cessation of smoking and drug treatment strategies form the basis of nephroprotection including the control of diabetes mellitus with metformin, sodium glucose transporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1) analogues and control of hypertension with blockade of the renin-angiotensin-aldosterone system (RAAS), hyperlipidemia, hyperphosphatemia and metabolic acidosis. The SGLT2 inhibitors are also effective for nondiabetic nephropathy. The elevated cardiovascular risk is further reduced by effective control of inflammatory rheumatic activity. Numerous conventional disease modifying antirheumatic drugs, especially methotrexate and the Janus kinase (JAK) inhibitors baricitinib and filgotinib, must mostly be adapted to the renal function. In contrast, biologics can be given in standard doses with the exception of anakinra. The increased cardiovascular risk currently limits the use of tofacitinib in patients with renal insufficiency. CONCLUSION: The antirheumatic medication should be modified and a complex nephroprotective treatment concept is mandatory in the management of patients with rheumatic disease and renal insufficiency, that in the best-case scenario can be guaranteed by a close interdisciplinary cooperation of rheumatologists and nephrologists.

Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial.

IMPORTANCE: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS: HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54371254.

Ulnar artery occlusion is predictive of digital ulcers in SSc: a duplex sonography study.

OBJECTIVES: To assess the prevalence and risk factors of ulnar artery occlusion (UAO) in an unselected SSc patient cohort and to determine whether UAO is associated with digital ulcers (DUs). METHODS: A total of 79 SSc patients and 40 'healthy' controls underwent colour duplex sonography of the radial and ulnar artery to compare blood flow velocity, resistive indices (RIs) and presence of occlusion and were followed for a mean of 53 months. RESULTS: In both, radial and ulnar arteries, peak systolic velocity (PSV) and end-diastolic velocity (EDV) were significantly lower and RI higher in SSc patients compared with controls (PSVrad: 40.1 vs 48.6 cm/s; PSVuln 38.2 vs 56.6 cm/s; EDVrad 3.8 vs 10.4 cm/s; EDVuln 3.0 vs 13.0 cm/s; RIrad 0.91 vs 0.82; RIuln 0.92 vs 0.80; all P < 0.01). Seventeen (21.5%) SSc patients had UAO (11 patients bilateral) compared with none in the control subjects. Patients with UAO had a significantly longer disease duration (170 vs 66 months, P < 0.001). At baseline, the prevalence of DU was not different in upper extremities with UAO [8/28 (28.6%)] compared with upper extremities without UAO [36/129 (27.9%)]. However, during follow-up new or recurrent DU occurred more often in upper extremities with UAO than in those without UAO [14/28 (50%) vs 24/113 (21.2%); relative risk (RR) = 2.4; 95% CI 1.4, 3.7; P = 0.002]. CONCLUSION: Blood flow is significantly decreased in radial and ulnar arteries in SSc. UAO is frequent and an important risk factor for the development of DUs in patients with SSc.

The renal resistance index is increased in mild-to-moderate obstructive sleep apnoea and is reduced under continuous positive airway pressure.

BACKGROUND: Impaired renal function has recently been reported in obstructive sleep apnoea (OSA). The underlying mechanisms, however, are not entirely understood. This study investigated the influence of mild-to-moderate OSA and its treatment on renal haemodynamics as assessed by the renal resistance index (RRI). METHODS: RRI has been measured by colour duplex ultrasound in 64 patients with newly diagnosed mild-to-moderate OSA and 61 controls without OSA at baseline and follow-up after 9.9 months. Treatment with continuous positive airway pressure was offered to all patients with OSA (apnoea/hypopnoea index ≥ 5/h). RESULTS: Increased values of RRI (≥ 1 SD [8.9%] above the age-adjusted normal value) were found in 41 out of 64 (64.0%) OSA patients when compared with 20 out of 61 (32.8%) controls (P < 0.001). The corresponding mean RRI was 70.50 ± 9.01 vs 66.51 ± 8.33 (P = 0.012). In multivariate analyses, the influence of OSA on RRI was independent from hypertension, diabetes mellitus, age and baseline renal function. At follow-up, RRI decreased only in patients with effective OSA treatment but remained unchanged in ineffectively treated OSA patients and controls. CONCLUSIONS: For the first time, this prospective controlled observational study demonstrates an impairment of renal haemodynamics in OSA as measured by an increased RRI. These changes of renal blood flow may identify OSA patients at high risk of declining renal function. Both parenchymal and vascular renal diseases are proposed as pathomechanisms for this association. An effective treatment of OSA resulted in a decreased RRI, suggesting an improvement in renal perfusion. Further studies are needed to elucidate the role of impaired renal haemodynamics in OSA.

Identification of α-tubulin as an autoantigen recognized by sera from patients with neuropsychiatric systemic lupus erythematosus.

In a previous study we found in 50% of patients with neuropsychiatric manifestations of systemic lupus erythematosus (NP-SLE) organ specific antibodies to 45-56 kD proteins in a 100,000 g supernatant (SN) from bovine brain mitochondria. Aim of the present study was to identify the corresponding target antigen. A 100,000 g SN from bovine brain mitochondria was applied to SDS-gel electrophoresis. A 50 kD band recognized by sera from patients with NP-SLE in the Western blot (WB) was excised from the gels and applied to mass spectrometry. The identified protein was expressed in Escherichia coli and retested against sera from eleven patients with NP-SLE (severe symptoms n=6, mild symptoms n=5), 26 SLE-patients without NP manifestations and 53 controls (patients with multiple sclerosis, epilepsy, healthy blood donors). Mass spectrometry of the 50 kD band revealed the presence of α-tubulin. Applying the recombinant α-tubulin in the WB, four of the eleven NP-SLE patients (36%), one of the 26 patients with SLE without NP manifestations (4%) and none of the 53 controls reacted with α-tubulin. The antibodies were more frequently found in patients with severe (50%) than with mild NP-SLE (20%). α-tubulin may be a novel marker autoantigen for a neuropsychiatric manifestation at least in a subgroup of patients with SLE. Whether anti-α-tubulin antibodies are of pathogenetic relevance has still to be clarified.

Abdominal pseudocysts following peritoneal dialysis-associated peritonitis: a report of 3 cases.

Common complications of peritoneal dialysis are peritonitis, leakages, hernias, catheter dislocation, and loss of ultrafiltration. We describe 3 cases of abdominal pseudocysts with progressive difficulty instilling and draining peritoneal dialysis fluid. The 3 patients had been treated with peritoneal dialysis for 1, 2, and 6 years. Two patients had experienced previous episodes of peritonitis and 1 had signs of peritonitis when the pseudocyst was first detected. In all 3 patients, ultrasound and computed tomographic scans, obtained because of progressive decreases in solute clearance, showed dialysate entrapped in a cyst that enclosed the inner tip of the Tenckhoff catheter. The cyst was resected in 2 patients, and the Tenckhoff catheter was removed in 1 patient. Histologic samples were not suggestive of encapsulating peritoneal sclerosis. Abdominal pseudocysts are a rare complication after peritoneal dialysis therapy, but are reported in 1% of patients with ventriculoperitoneal shunts. The outcome of our described patients was good, although they had to be switched to hemodialysis therapy.

Plasma complement 3d levels in the early phase after pancreas transplantation.

BACKGROUND: Rejection and graft thrombosis are the main reasons leading to early graft loss after pancreas transplantation. Identifying parameters that forecast these complications would be helpful. Complement activation might occur during rejection and thrombosis leading to elevated complement split products. This prospective study analyses the plasma complement 3d (C3d) levels in the early post-pancreas transplant (PTx) period to test its predictive value to determine rejection and thrombosis. MATERIAL/METHODS: Plasma C3d levels were measured after isolated PTx (n=2), simultaneous pancreas and kidney transplantation (SPKT, n=20) and pancreas re-transplantation (n=3). RESULTS: Pancreas rejection was observed in 3, pancreas thrombosis in 4, and kidney rejection in 7 patients. Patients after isolated kidney transplantation (IKT) served as controls. Within 40 days after PTx and IKT C3d levels were significantly elevated compared to volunteers and long-term kidney transplant recipients (p<0.001). C3d levels increased during 40 days after PTx, but dropped after IKT. During pancreas rejection episodes mean C3d levels were elevated (14.0+/-3.5 mg/l) compared to those obtained during graft thrombosis (9.1+/-1.6 mg/l; p=0.012) or periods of normal graft function (10.6+/-1.9 mg/l; p=0.046). A slight elevation of C3d was observed during kidney rejection episodes in SPKT (12.7+/-2.0 mg/l; p=0.074) but not during kidney rejection after IKT. CONCLUSIONS: C3d plasma levels increase during episodes of pancreas rejection and decrease in pancreas transplant thrombosis. However, single C3d values have no predictive diagnostic value after SPKT.

High-dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients.

BACKGROUND: Vitamin D has emerged as an important survival factor in patients with chronic kidney disease. Non-activated vitamin D may also have beneficial effects on bone, cardiovascular and immune functions. Cholecalciferol is the prevalent non-activated vitamin D in Europe, but there is no valid prospective data available about its use in haemodialysis patients. Thus, we initiated a prospective study to evaluate dosing, safety and tolerability of cholecalciferol supplementation in haemodialysis patients. METHODS: The prospective study included 64 haemodialysis patients. During replenishment phase patients received 20 000 IU cholecalciferol/week for 9 months. In the open maintenance phase (15 months), patients were randomized to a treated group (20 000 IU cholecalciferol/month) and an untreated group, which did not receive cholecalciferol. RESULTS: Calcidiol [25(OH)D] deficiency (<37.5 nmol/l; <15 microg/l) was detected in 61/64 patients (95%). During the replenishment phase, calcidiol increased significantly from 16.65 +/- 9.6 to 79.48 +/- 27.15 nmol/l (6.66 +/- 3.84 microug/l to 31.79 +/- 10.86 microg/l) (P < 0.001). Recommended levels (>75 nmol/l; >30 microg/l; K/DOQI) were achieved in 57% of patients. Calcium increased from 2.28 +/- 0.17 to 2.37 +/- 0.19 mmol/l (9.1 +/- 0.69 mg/dl to 9.49 +/- 0.75 mg/dl) (P<0.01). Phosphorus, calcium-phosphorus product and parathyroid hormone showed no significant changes. Fifty-nine patients progressed to the maintenance phase. Analysis per protocol showed a significant drop of calcidiol in the treated [83.98 +/- 31.73 versus 78.5 +/- 38.75 nmol/l (33.59 +/- 12.69 versus 31.4 +/- 15.5 microg/l) (P < 0.001)] and untreated groups [86.35 +/- 40.75 versus 53.4 +/- 26.2 nmol/l (34.54 +/- 16.3 versus 21.36 +/- 10.48 microg/l) (P < 0.001)]. The comparison of the treated and the untreated groups showed no significant differences at the beginning of the maintenance phase: 83.98 +/- 31.73 versus 86.35 +/- 40.75 nmol/l (33.59 +/- 12.69 versus 34.54 +/- 16.3 microg/l). At the end they differed significantly: 78.5 +/- 38.75 versus 53.4 +/- 26.2 nmol/l (31.4 +/- 15.5 versus 21.36 +/- 10.48 microg/l) (P < 0.001). CONCLUSION: Vitamin D deficiency is present in a majority of haemodialysis patients. Supplementation with cholecalciferol is safe, well tolerated and reasonable to replenish vitamin D stores in haemodialysis patients. However, only 57% of patients achieved recommended calcidiol levels, thus favouring additional dose-finding studies.

Hypercalcemia after transplant nephrectomy in a hemodialysis patient: a case report.

INTRODUCTION: Hypercalcemia is a complication often seen in chronic hemodialysis patients. A rare cause of this condition is sarcoidosis. Its highly variable clinical presentation is challenging. Especially in patients suffering chronic kidney graft failure the nonspecific constitutional symptoms of sarcoidosis like fever, weight loss, arthralgia and fatigue may be easily misleading. CASE PRESENTATION: A 51 year old male developed hypercalcemia, arthralgia and B-symptoms after explantation of his kidney graft because of suspected acute rejection. The removed kidney showed vasculopathy and tubulointerstitial nephritis, which had not been overt in the biopsy taken half a year earlier. Despite explantation and withdrawal of the immunosuppression the patient's general condition deteriorated progressively. A rapid rise in serum calcium finally provoked us to check for sarcoidosis. CT scans of the lungs, broncho-alveolar-lavage and further lab tests confirmed the diagnosis. CONCLUSION: This case demonstrates that withdrawal of immunosuppressive drugs sometimes unmasks sarcoidosis. It should be considered as differential diagnosis even in hemodialysis patients, in whom other reasons for hypercalcemia are much more common.

Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome--a single-centre experience and review of the literature.

BACKGROUND: The introduction of sirolimus as an immunosuppressive drug for renal transplantation has lead to an increase of unexplained interstitial pneumonitis. METHODS: Out of a cohort of 115 patients receiving sirolimus for prophylaxis of renal and/or pancreas transplant rejection, 11 patients with interstitial pneumonitis were identified. Medical records and published case series were reviewed to identify risk factors associated with the occurrence of pneumonitis. RESULTS: Eleven out of 80 patients (14%) with late switch to sirolimus developed pneumonitis, in contrast to none of the 35 patients with de novo use of sirolimus. The mean sirolimus trough level at presentation was 16.7 mug/l (range: 6.2-38.7 mug/l). Glomerular filtration rate (GFR) was significantly lower in patients with pneumonitis compared to controls (mean 21.3 +/- 3.9 ml/min vs 38.65 +/- 2.14 ml/min P = 0.002). Two patients needed haemodialysis shortly before pneumonitis was diagnosed. In a multivariate analysis only serum creatinine and GFR were independent predictors for pneumonitis. Sirolimus was discontinuated in five patients and the dose reduced in the other patients. Pneumonitis resolved within 14-28 days in all patients. One patient who had continued low-dose sirolimus treatment relapsed after 5 months, the other five patients had no relapse over a period of 15-48 months. Pooled analysis of our data and other published case series showed that the frequency of pneumonitis in patients with de novo use of sirolimus is significantly lower than in patients with late switch [5/133 (4%) vs 46/326 (14%) patients, P = 0.0024]. CONCLUSIONS: Late switch to sirolimus and impaired renal function are risk factors for pneumonitis. A sirolimus blood trough level above 12 mug/l may increase the risk, but pneumonitis may also occur at blood trough levels as low as 6 mug/l. Since pneumonitis may recur during low-dose sirolimus treatment, discontinuation of sirolimus appears to be the safest treatment option.

A German family with glucocorticoid-remediable aldosteronism.

BACKGROUND: The prevalence of primary hyperaldosteronism (PHA) in the hypertensive population has increased in recent years. Glucocorticoid-remediable aldosteronism (GRA) is a rare monogenic form of PHA. Here we report a German family with GRA. Since the phenotype of GRA varies widely, we asked whether recommended algorithms for PHA diagnosis distinguish GRA from other forms of PHA. METHODS: Plasma aldosterone (pg/ml) and renin (pg/ml) levels were determined in three hypertensive family members with GRA before and after sodium loading with 2 l of saline (0.9%), during posture and after 1 week of 2 mg dexamethasone daily. 24 h blood pressure and urinary excretion of aldosterone, cortisol precursors and metabolites were measured before and after dexamethasone. Southern blot hybridization and long-range PCR were performed to identify the chimeric gene. RESULTS: All three affected patients had normal potassium levels but markedly increased aldosterone/renin ratios of 472, 213 and >322 (normal range<50) indicating PHA. Sodium loading failed to lower plasma aldosterone below the threshold of 50 pg/ml in all patients. During posture, aldosterone increased in one but decreased in both other GRA patients. Elevated 18-hydroxycortisol, free aldosterone and its main metabolite aldosterone-18-glucuronid and tetrahydroaldosterone returned to normal range after 1 week dexamethasone in all patients, but blood pressure was reduced only in one patient. The chimeric gene was identified in affected family members by Southern blot and PCR. CONCLUSIONS: The aldosterone/renin ratio is a valid screening and sodium loading a valid confirmation test in GRA. Determination of elevated urinary excretion of specific aldosterone metabolites and identification of the chimeric gene are mandatory since a lacking blood pressure response to dexamethasone can be misleading.

Renal toxicity after radionuclide therapy.

During the past 10 years, a variety of radiolabeled monoclonal antibodies, antibody fragments, and low-molecular- weight oncophilic peptides have been used to deliver radioactivity to target cells for therapeutic purposes. The high and persistent localization of several of these radiolabeled molecules in the kidneys raised concern about potential renal radiation toxicity compromising therapeutic effectiveness. In particular, radiolabeled peptides, such as yttrium-90-labeled synthetic somatostatin analogues, have initiated a discussion on the safety profiles of the various somatostatin derivatives in recent clinical trials. In general, the toxicity risk seems to depend on the characteristics of the oncophilic molecule, such as the molecular weight, electric charges and clearance pathways as well as the chemical and physical characteristics of the applied radionuclide. Encouraging results for the prevention of radiation-induced renal damage by radiolabeled peptides have been obtained by co-infusion of positively charged amino acids. The available literature on nephrotoxicity after radiolabeled peptide therapy is reviewed, and therapeutic options that have become available as a result of greater insights into putative pathogenic mechanisms are discussed.

Impact of in vivo complement activation and cryoglobulins on graft outcome of HCV-infected renal allograft recipients.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is closely associated with mixed cryoglobulinemia. Cryoglobulins can activate complement leading to vascular damage. We examined whether cryoglobulinemia and complement turnover is associated with HCV infection in renal transplant recipients and whether this has an adverse effect on graft outcome. METHODS: Sera and fresh plasma from 31 HCV-RNA-positive patients after renal transplantation (group I) were studied for cryoglobulins, complement hemolytic activity (CH50), and complement split product C3d. In total, 80 HCV-negative renal transplant recipients (group II) and 72 untreated patients with chronic hepatitis C (group III) without renal transplantation served as controls. RESULTS: Cryoglobulins were detected in 45, 28, and 26% of the patients in group I, II, and III, respectively. A high cryocrit ( > 5%) was present only in patients of group III (p < 0.01%). Mean CH50 values were lower and C3d levels higher in HCV-positive patients (group I and III) compared with HCV-negative patients (p < 0.0001). Cryoglobulins were not associated with extrahepatic manifestations or graft dysfunction, except in five patients of group III demonstrating cryoglobulinemic vasculitis. HCV-positive renal transplant recipients with signs of complement activation showed a significantly greater increase of serum creatinine (0.88 +/- 1.14 mg/dL) when compared with baseline than patients without complement activation (0.34 +/- 0.37 mg/dL; p = 0.035). There was also a tendency toward a higher extent of proteinuria in patients with complement activation (1.38 +/- 2.17 g/d vs. 0.50 +/- 0.77 g/d; p = 0.25, NS). CONCLUSIONS: Cryoglobulins are common in renal allograft recipients, but do not affect graft function. However, complement activation appears to be involved in chronic allograft dysfunction in HCV-infected recipients.