Sustained Improvement In Renal Function Research Articles

Sustained improvement in renal function with palopegteriparatide in adults with chronic hypoparathyroidism: 2-year results from the phase 3 PaTHway trial

Sustained improvement in renal function with palopegteriparatide in adults with chronic hypoparathyroidism: 2-year results from the phase 3 PaTHway trial

Raising Awareness Towards Underdiagnosed Renal Hypouricemia: A Case Report

Renal hypouricemia (RHUC) is an autosomal recessive disease caused by the dysfunction of uric acid (UA) transporters in the proximal tubule causing increased fractional excretion of uric acid (FEUA). It is associated with mutations of SLC22A12 that codifies for URAT1, involved in RHUC type 1, or SLC2A9 which codifies for GLUT9 and is involved in RHUC type 2. We present the case of a man diagnosed with RHUC type 2 following hospitalization for acute kidney injury (AKI). A 43-year-old was hospitalized due to AKI after a 20 km walk at an outdoor temperature of 30°C. On the objective examination, he was dehydrated. Blood tests presented severe azotemia (creatininemia 16.43 mg/dL, uremia 254 mg/dL), UA 3.6 mg/dL, fosfatemia 6 mg/dL, Na 138 mEq/L, K 4.2 mEq/L, Cl 102 mEq/l, arterial gasometry with pH 7.35, pCO2 36 mmHg, HCO3 20 mmol/L, lactates 1.4 mmol/L. Urine test with proteinuria and unremarkable sediment. His kidneys had foci of microlithiasis. He started vigorous fluid therapy and sustained improvement in renal function was seen, with no need for renal function replacement therapy. The subsequent evaluation showed hypouricemia <1.5 mg/dL and FEUA of 32.5% (normal range 5.5%-8.5%). The molecular study identified the variant c.1221del p.(His407Glnfs*8) in the SLC2A9 gene in homozygosis, which established the diagnosis of RHUC type 2. This case highlights the importance of recognizing hereditary RHUC to prevent its manifestations, including exercise-induced AKI, nephrolithiasis, nephrocalcinosis, and more rarely, progression to stage 5 CKD. Its diagnosis should be considered in individuals with serum UA <2 mg/dL and elevated FEUA. Additionally, it should be confirmed by the identification of mutations in homozygous or compound heterozygous in SLC22A12 or SCL2A9. Treatment includes xanthine oxidoreductase inhibitors and adequacy of physical activity. The use of uricosuric antihypertensive drugs whose mechanism of action involves blocking the URAT1 transporter should be avoided.

A Case of Recurrent Ovarian Cancer with Renal Dysfunction Associated with the Use of Olaparib

Olaparib (ORB) is known not to largely affect renal function due to its specific pharmacological mechanism, and there are no reports on renal dysfunction associated with the drug. The patient was found to have been diagnosed with recurrent ovarian cancer. She started therapy with bevacizumab (BEV). Unfortunately, BEV was discontinued due to the development of progressive renal dysfunction with proteinuria. Therefore, she started the administration of ORB. However, after switching to ORB, her renal dysfunction progressed. Renal histopathology revealed membranoproliferative glomerulonephritis (MPGN) and thrombotic microangiopathy (TMA). During the clinical course, her renal function deteriorated after the administration of ORB and improved after the drug was discontinued because of bone marrow suppression. Moreover, sustained improvement of renal function was observed after complete discontinuation of the drug. This case is considered to be the first report of renal dysfunction due to ORB. In the recent PAOLA-1 trial, the efficacy and toxicity profiles of the combination of BEV and ORB were superior to those of BEV alone. The combination of BEV and ORB is now the first-line treatment for ovarian cancer based on this result. In the present case, ORB was administered to a patient with BEV-induced renal dysfunction, resulting in further aggravation of the renal dysfunction. Here we report this case because of the adverse reaction that should be noted when ORB and BEV are used in combination therapy, which is expected to be more popular, based on the PAOLA-1 trial results.

P226 LONGITUDINAL EVALUATION OF CONGESTION AND RENAL FUNCTION IN ADVANCED HEART FAILURE PATIENTS TREATED WITH A LEFT VENTRICULAR ASSIST DEVICE

Abstract Introduction In patients affected by advanced heart failure (advHF) long term mechanical support with left ventricular assist devices (LVADs) is a established therapeutic option. Congestion and renal function in pts treated with a LVAD require expert management. Aim Describe the longitudinal trend of congestion and renal function during a 12th follow–up in advHF pts treated with a LVAD, examine the correlation between congestion and renal function, study predictors of sustained improvement of congestion and renal function. Methods retrospective single–centre analysis of 39 pts treated with a LVAD and followed in ASST–PG23 Hospital for at least 12 months. Biochemical, echocardiographic and clinical parameters were collected at specific time points from baseline to 12 months after hospitalization during which a LVAD was implanted. Congestion was studied with BNP, bilirubin, haematocrit and daily diuretics dosage. Renal function was studied with absolute changes of eGFR (Cockcroft–Gault). Primary endpoint was sustained improvement of congestion and renal function, derived after comparing baseline pre–LVAD and 12th month parameters. Results congestion improved early after LVAD implantation, with steep and high reduction of BNP, bilirubin and daily diuretics dosage. The improvement was higher in those pts with a baseline BNP>median. Bilirubin, haematocrit and daily diuretics dosage showed statistically significant correlations with BNP. Sustained improvement of congestion was present in 59% pts, in particular in those with higher baseline BNP (p = 0.04 after χ²–test). Renal function showed an early steep improvement from baseline pre–LVAD to discharge, more significant in those pts with baseline CKD; during the following months renal function did not show significant changes. Sustained improvement of renal function was present in 54% pts, in particular in those with baseline CKD (p = 0.002 after χ²–test). No significant correlations were found after comparing the trend of congestion and renal function. At multivariable logistic regression, no significant predictors were found for sustained improvement of congestion or renal function. Conclusions A multiparametric evaluation of congestion in pts with a LVAD is feasible. The benefit derived from LVAD support appears to be higher in those pts with a baseline higher risk, both in term of congestion and renal function. No significant correlation between the trend of congestion and renal function was found.

Beneficial Effects of Vasopressin Compared With Norepinephrine on Renal Perfusion, Oxygenation, and Function in Experimental Septic Acute Kidney Injury

To compare the effects of restoring mean arterial pressure with vasopressin or norepinephrine on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, and renal function in ovine septic acute kidney injury. Interventional Study. Research Institute. Adult Merino ewes. Flow probes were implanted on the pulmonary and renal arteries (and the mesenteric artery in sheep that received vasopressin). Fiber-optic probes were implanted in the renal cortex and medulla to measure tissue perfusion and oxygen tension (PO2). Conscious sheep were administered Escherichia coli to induce septic acute kidney injury. Vasopressin (0.03 IU/min [0.03-0.05 IU/min]; n = 7) or norepinephrine (0.60 μg/kg/min [0.30-0.70 μg/kg/min]; n = 7) was infused IV and titrated to restore baseline mean arterial pressure during 24-30 hours of sepsis. Ovine septic acute kidney injury was characterized by reduced mean arterial pressure (-16% ± 2%) and creatinine clearance (-65% ± 9%) and increased renal blood flow (+34% ± 7%) but reduced renal medullary perfusion (-44% ± 7%) and PO2 (-47% ± 10%). Vasopressin infusion did not significantly affect renal medullary perfusion or PO2 and induced a sustained (6 hr) ~2.5-fold increase in creatinine clearance. Vasopressin reduced sepsis-induced mesenteric hyperemia (+61 ± 13 to +9% ± 6%). Norepinephrine transiently (2 hr) improved creatinine clearance (by ~3.5-fold) but worsened renal medullary ischemia (to -64% ± 7%) and hypoxia (to -71% ± 6%). In ovine septic acute kidney injury, restoration of mean arterial pressure with vasopressin induced a more sustained improvement in renal function than norepinephrine, without exacerbating renal medullary ischemia and hypoxia or reducing mesenteric blood flow below baseline values.

MTOR Inhibition and Clinical Transplantation: Liver.

The evidence base concerning use of mammalian target of rapamycin (mTOR) inhibitor therapy after liver transplantation is evolving rapidly, clarifying their benefits and disadvantages in different clinical scenarios. The H2304 trial showed that starting everolimus at 1 month posttransplant, with reduced tacrolimus, achieves a sustained improvement in renal function versus standard tacrolimus-based therapy, with at least equivalent immunosuppressive efficacy. Randomized studies evaluating early discontinuation of calcineurin inhibitor (CNI) therapy after introduction of an mTOR inhibitor consistently demonstrated a substantial improvement in renal function versus standard CNI therapy. However, concomitant mycophenolic acid is advisable to avoid an increase in mild biopsy-proven acute rejection, and induction with an interleukin-2 receptor antagonist may also be helpful. High-quality robust data regarding prevention of posttransplant malignancies under mTOR inhibitors is lacking in liver transplantation, although there are some indications of benefit. In maintenance patients, robust data are limited regarding mTOR inhibitor initiation in response to deteriorating renal function or other indications but late conversion (>1 year) appears ineffective. Rates of mTOR inhibitor discontinuation due to adverse events are high, affecting at least a quarter of patients. In conclusion, the evidence base for use of mTOR inhibitors early posttransplant to support CNI reduction now convincingly demonstrates a renal advantage, but adequate adjunctive immunosuppression is essential to preserve efficacy.

Azathioprine-induced interstitial nephritis in an anti-neutrophil cytoplasmic antibody (ANCA) myeloperoxidase (MPO) vasculitis patient.

Azathioprine (AZA) is used in a wide array of autoimmune diseases, still corresponding to the mainstay maintenance therapy in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Although generally well-tolerated, several side effects are recognized. We report the case of a 50-year-old Caucasian man with kidney-limited ANCA myeloperoxidase (MPO) vasculitis who presented with general malaise, fever, worsening renal function, and elevated inflammatory markers 2 weeks after the initiation of therapy with oral AZA. Although a disease relapse was suspected, renal biopsy revealed an eosinophilic infiltrate, suggestive of acute interstitial nephritis. After suspension of AZA, a sustained improvement of renal function and normalization of inflammatory markers was observed. A diagnosis of allergic interstitial nephritis secondary to AZA was established, corresponding to the first biopsy-proven case described in an ANCA MPO vasculitis patient. Although rare, renal toxicity of AZA must be present in the clinician's mind, avoiding the straightforward assumption of disease relapse in the case of worsening renal function.

Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence.

In this study, we aimed to systematically review available literature on the efficacy of eculizumab for the treatment of renal involvement in patients with systemic lupus erythematosus (SLE). We conducted a literature search developed a priori, to identify articles reporting clinical experience with the use of eculizumab in SLE patients, focusing on renal involvement. The search strategy was applied to Ovid MEDLINE, EMBASE, In-Process and Other Non-Indexed Citation, Cochrane Central Register of Controlled Trials and Scopus from 2006 to present. Abstracts from EULAR and ACR congresses were also screened. We included six publications describing the renal outcome in SLE patients receiving eculizumab. Five out of six cases described the occurrence of thrombotic microangiopathy (TMA) in renal biopsies of patients with known SLE; three cases with biopsy-proven lupus nephritis (LN) and two patients with SLE-related antiphospholipid syndrome without histologic evidence of LN. One study reported the outcome of a patient with severe refractory LN successfully treated with eculizumab. All patients, regardless of the presence of concomitant LN, presented with severe hypocomplementemia and renal function impairment. All patients showed a sustained improvement of renal function and normalization of complement parameters after treatment with eculizumab[median follow-up 9 months (1-17)]. Despite the limitations of the currently available evidence, existing data are promising and provide preliminary support for the use of eculizumab in selected cases of SLE with renal involvement, especially in the presence of TMA, or in patients with refractory LN.

Rituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis: Case Report and Review of the Literature.

Immunoglobulin type gamma 4 (IgG4)-related disease is a relatively newly described clinical entity characterized by a distinctive histopathological appearance, increased numbers of IgG4 positive plasma cells and often, but not always, elevated serum IgG4 concentrations. The most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis marked with proteinuria, hematuria, decreased kidney function, hypocomplementemia, and radiologic abnormalities. Renal biopsy characteristics include dense lymphoplasmacytic tubulointerstitial nephritis that stains for IgG4, storiform fibrosis, and immune complex deposition in the interstitium and along tubule basement membranes. Treatment traditionally consists of prolonged glucocorticoids but cases refractory to glucocorticoids have been reported.We report a case of a 58-year-old Caucasian man who presented with fatigue, 50 pound weight loss, dyspnea, lymphadenopathy, and nephromegaly. The patient was first misdiagnosed as chronic interstitial nephritis secondary to renal sarcoid and was treated with repeated doses of prednisone. On his third relapse, he underwent a repeat renal biopsy and a diagnosis of IgG4-tubulointerstitial nephritis was confirmed. He was refractory to treatment with prednisone. The patient received Rituximab and had prompt sustained improvement in renal function. At 1 year post Rituximab treatment, his serum creatinine remains at baseline and imaging study revealed reduction in his kidney size.This is the first case report using Rituximab as a steroid sparing option for refractory IgG4-tubulointerstitial nephritis. More information is needed on the long-term effects of using of B-cell depleting agents for glucocorticoid resistant IgG4-tubulointerstitial nephritis.

Relationship Between Renal Function and Extracorporeal Membrane Oxygenation Use: A Single-Center Experience

The effects of extracorporeal membrane oxygenation (ECMO) support on renal function in children with critical illness are unknown. The objective of this study was to investigate the impact of ECMO on renal function among children in different age groups. We performed a single-center retrospective observational study in critically ill children ≤ 18 years supported on ECMO for refractory cardiac or pulmonary failure (2006-2012). The patient population was divided into four age groups for the purpose of comparisons. The Acute Kidney Injury Network's (AKIN's) validated, three-tiered staging system for acute kidney injury was used to categorize the degree of worsening renal function. Data on patient demographics, baseline characteristics, renal function parameters, dialysis, ultrafiltration, duration of mechanical cardiac support, and mortality were collected. Comparisons of baseline characteristics, duration of mechanical cardiac support, and renal function were made between the four age groups. During the study period, 311 patients qualified for inclusion, of whom 289 patients (94%) received venoarterial (VA) ECMO, 12 (4%) received venovenous (VV) ECMO, and 8 (3%) received both VV and VA ECMO. A total of 109 patients (36%) received ultrafiltration on ECMO, 58 (19%) received hemodialysis, and 51 (16%) received peritoneal dialysis. There was a steady and sustained improvement in renal function in all age groups during the ECMO run, with the maximum and longest-sustained improvement occurring in the oldest age group. Proportions of patients in different AKIN stages remained similar in the first 7 days after ECMO initiation. We demonstrate that renal dysfunction improves early after ECMO support. Irrespective of the underlying disease process or patient age, renal function improves in children with pulmonary or cardiac failure who are placed on ECMO.

(509) - Age-Related Decline in Lung Function in Patients Without CLAD After Double Lung Transplantation

This improvement was maintained at both 1 and 3 years post-conversion (p< 0.001). In regards to pulmonary function, FEV1 decreased from the time of sirolimus initiation to 3 years post-conversion (p= 0.042), mean decrease 0.23 L (95% CI, 0.01-0.46). However, early conversion to sirolimus (< 6 months post-transplant) resulted in a trend towards improved FEV1 at 3 years (+0.017 L in the early conversion group versus -0.44 L in the late conversion group, p= 0.052). The sirolimus discontinuation rate for reasons other than death was 17.8%. Conclusion: Sirolimus is a viable immunosuppressant option after lung transplant, which successfully allows for the reduction or withdrawal of the CNI, resulting in sustained improvement in renal function. The antifibrotic properties of sirolimus may allow it to slow the progression of BOS, especially when initiated within the first 6 months of transplant.

(146) - Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin- Receptor Blockers (ARBs) during CF-LVAD Support Are Associated with Sustained Improvement in Renal Function

s S59 Austria; 2Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria; 3Center for Med. Phys. & Biomed. Eng. L. B. Cluster for Cardiovasc. Res. Dept of Cardiac Surgery, Medical University of Vienna, Vienna, Austria; 4Rehabilitation Clinic Felbring, Muthmannsdorf, Austria. Purpose: Left ventricular assist devices (LVAD) are increasingly implanted for long support times and destination therapy. Therefore, focus is shifting from pure survival to quality of life and physical performance. The present study was designed to evaluate the development of exercise capacity within the first 2 years of LVAD support. Methods: Data obtained during rehabilitation of 12 patients undergoing LVAD implantation for terminal heart failure between June 2010 and July 2012 were retrospectively analyzed (age 57±10 y, female: 17%, HeartWareHVAD: 58%, Thoratec-HeartmateII: 42%, INTERMACS Level I: 42%, II: 17%, III: 25% and IV-VII: 16%). Patients underwent cardiac rehabilitation including cardiopulmonary stress tests twice, after LVAD implantation and a second time after 1 to 2 years. Study endpoints were peak-workload and peak-VO2 obtained with spiroergometry. Results: Patients were admitted to the rehabilitation clinic the first time 6.1±2.5 weeks after LVAD implantation and the second time at 1.7±0.4 years post-implant. An increase in peak-workload was observed between the two rehabilitation periods (81.6±20.8 vs. 55.1±23.6 W, p= 0.001), which reflected an overall improvement of muscular strength and coordination observed. However, the peak-VO2 did not increase, even slightly decreased although not significantly (11.1±2.0 vs. 12.5±2.9 ml/min/kg, p= 0.223). A probable reason for this decrease was a considerable gain of body weight (95.8±10.9 vs. 84.9±11.1 kg, p< 0.001) in the same observation period. Conclusion: Within the first two years of LVAD support patients show a general improvement in peak exercise workload but no changes in the peak oxygen uptake. The increase in the aerobic capacity seems limited by the still suboptimal pumping function of heart and LVAD combined.

Long-Term Exposure to Belatacept in Recipients of Extended Criteria Donor Kidneys

Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein–Barr virus (EBV(−)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m2. Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time.

Telbivudine Improves Renal Function in Patients With Chronic Hepatitis B

There is a close relationship between chronic hepatitis B virus infection and chronic renal disease. We analyzed changes in renal function using different markers of glomerular filtration rate (GFR) in multiple studies of telbivudine treatment of patients with chronic hepatitis B virus infection. We used serum creatinine-based equations (ie, Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration) to estimate GFR (eGFR) in adults with chronic hepatitis B virus infection and compensated liver disease who participated in a phase III, randomized, double-blind study comparing the efficacy and safety of telbivudine (600 mg/d) and lamivudine (100 mg/d) for 2 years (the GLOBE study) and in long-term extension studies (4-6 years), as well as in patients with decompensated cirrhosis (2 years). eGFRs calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations were concordant, indicating improved renal function in telbivudine-treated patients during the 2-year GLOBE study (there was an 8.5% increase in mean eGFR, based on the Modification of Diet in Renal Disease equation). Improved renal function was maintained for 4-6 years. Increased eGFR with telbivudine treatment was also observed in patients at increased risk for renal impairment: patients with baseline eGFRs of 60-89 mL/min/1.73 m(2) (+17.2%), older than 50 years (+11.4%), and with liver fibrosis/cirrhosis (+7.2% for patients with Ishak fibrosis score at 5-6). In decompensated patients with high renal risk, eGFR was also improved on telbivudine (+2.0%). In global trials of patients with compensated and decompensated cirrhosis, long-term telbivudine therapy was associated with a sustained improvement of renal function-particularly among patients with increased risk of renal impairment. The mechanisms of this renal protective effect remain to be determined.

Everolimus immunosuppression in de novo heart transplant recipients: What does the evidence tell us now?

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.

Clinical Markers Associated With Sustained Improvement in Renal Function After 1-Year of Continuous Flow Left Ventricular Assist Device (CF-LVAD) Support

Clinical Markers Associated With Sustained Improvement in Renal Function After 1-Year of Continuous Flow Left Ventricular Assist Device (CF-LVAD) Support

Sirolimus Conversion in Liver Transplant Recipients With Calcineurin Inhibitor-Induced Complications: Efficacy and Safety

To evaluate the efficacy and safety of conversion from calcineurin inhibitors to sirolimus among liver transplant recipients with calcineurin inhibitor-induced complications. After receiving liver transplants, 25 patients with calcineurin inhibitor-induced complications (22 renal dysfunction and 3 new-onset diabetes mellitus) were converted from sirolimus to tacrolimus. The serum creatinine, sirolimus trough level, liver function, acute rejection episodes, and drug-related adverse effects were monitored. The patients were followed for 12 to 50 months (median, 25 months). The renal function of the 22 patients with renal dysfunction improved after sirolimus conversion. The serum creatinine levels were significantly lower at 3 months after conversion versus before conversion (113.2 ± 21.8 μmol/L vs 163.2 ± 45.3 μmol/L; P < .05). At the end of the follow-up, the average serum creatinine level was 101.9 ± 23.4 μmol/L among the 20 living recipients. Diabetes also was under control in 3 diabetic recipients after the conversion. Four patients experienced episodes of acute rejection, and intravenous steroid bolus therapy was administered in 2 of them. No graft was lost because of acute rejection. The adverse effects of sirolimus included hyperlipidemia (7/25), anemia (8/25), and mouth ulcers (9/25). All these adverse effects were relieved after a short-term symptomatic therapy, and no patient was withdrawn from the conversion trial. Sirolimus monotherapy is effective and safe in liver transplant recipients. Conversion to sirolimus was associated with a sustained improvement in renal function and diabetes mellitus without an increased incidence of acute rejection episodes.

788 Preoperative Optimization Contributes to Sustained Improvement in Renal Function with LVAD Therapy

788 Preoperative Optimization Contributes to Sustained Improvement in Renal Function with LVAD Therapy

Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36 months after transplantation

Early conversion to a calcineurin-inhibitor (CNI)-free maintenance immunosuppression with sirolimus (SRL), mycophenolate mofetil (MMF) and steroids was associated with an improved 1-year renal function as compared with a cyclosporine (CsA)-based regimen (SMART core-study). This observational follow-up describes 132 patients followed up within the SMART study framework for 36months. At 36months, renal function continued to be superior in SRL-treated patients [ITT-eGFR(@36m) : 60.88 vs. 53.72 (CsA) ml/min/1.73m(2) , P=0.031]. However, significantly more patients discontinued therapy in the SRL group 59.4% vs.42.3% (CsA). Patient [99% (SRL) vs.97% (CsA) and graft 96% (SRL) vs.94% (CsA)] survival at 36months was excellent in both arms. There was no difference in late rejection episodes. Late infections and adverse events were similar in both arms except of a higher rate of hyperlipidemia in SRL and a higher incidence of malignancy in CsA-treated patients. In a multivariate analysis, donor age >60years, S-creatinine at conversion >2mg/dl, CMV naïve(-) recipients and immunosuppression with CsA were predictive of an impaired renal function at 36months. Early conversion to a CNI-free SRL-based immunosuppression is associated with a sustained improvement of renal function up to 36months after transplantation. Patient selection will be key to derive long-term benefit and avoid treatment failure using this mTOR-inhibitor-based immunosuppressive regimen.

A case of zoledronate-induced tubulointerstitial nephritis with Fanconi syndrome

A 54-year-old female underwent mastectomy in 1992 for breast cancer, but later developed liver metastasis in 2004, which was treated with docetaxel for a short period, and then discontinued due to nausea. Bone metastasis diagnosed in 2005 was treated with the combination of trastuzumab and zoledronate (4 mg/month) as well as radiotherapy. Progressive hypokalemia and renal dysfunction were observed since 2006 and the patient was admitted to our department in 2009 for further management of hypokalemia (serum potassium 2.2 mEq/L) and renal dysfunction (serum creatinine: 2.0 mg/dL). Accelerated potassium excretion and metabolic acidosis of the normal anion gap were observed and the patient was diagnosed with hypokalemia associated with renal tubular acidosis. Moreover, development of glucosuria, hypophosphatemia, hyperphosphaturia, hyponatremia, hypouricemia, and high β2-microglobulin/NAG, together with histopathological findings compatible with renal tubular injury/interstitial nephritis on renal biopsy, allowed the diagnosis of Fanconi syndrome. Because the syndrome was considered to be induced by zoledronate based on the onset and clinical course, we stopped zoledronate. However, she continued the ambulatory chemotherapy with trastuzumab. This resulted in immediate and sustained improvement in renal function. To our knowledge, this is the first report of zoledronate-induced interstitial nephritis-Fanconi syndrome and indicates the close monitoring of renal function to avoid potential nephrotoxicity of zoledronate.