Proteinuria and renal transplantation

The occurrence of proteinuria in transplant patients is a marker of poor prognosis. The augmentation of proteinuria is associated with an increased risk of patient death and graft loss. Even a low-level urinary protein excretion (0.5 g/d) has a highly significant negative impact on graft survival whether it is observed 1 or 3 months after transplantation. Urinary albumin excretion rate has also a major effect on risks of graft loss and death with functional kidney, macro-albuminuria increasing the risks of respectively 16.4 and 4.12 times comparatively to micro-albuminuria, which itself multiplies the risks by 14.2 and 5.5 respectively, compared to normo-albuminuria. In terms of factors causing proteinuria apparition, the role of proliferation signal inhibitors has been recently observed. Sirolimus, especially at high dose, in particular can induce the occurrence of proteinuria, which is reversible with treatment discontinuation, but only with a partial recovery of the renal function. Proteinuria may be explained by a direct glomerular impact of sirolimus on several podocyte markers.     

mToR inhibitors-induced proteinuria: mechanisms, significance, and management

Massive urinary protein excretion has been observed after conversion from calcineurin inhibitors to mammalian target of rapamycin (mToR) inhibitors, especially sirolimus, in renal transplant recipients with chronic allograft nephropathy. Because proteinuria is a major predictive factor of poor transplantation outcome, many studies focused on this adverse event during the past years. Whether proteinuria was due to sirolimus or only a consequence of calcineurin inhibitors withdrawal remained unsolved until high range proteinuria has been observed during sirolimus therapy in islet transplantation and in patients who received sirolimus de novo. Podocyte injury and focal segmental glomerulosclerosis have been related to mToR inhibition in some patients, but the pathways underlying these lesions remain hypothetic. We discuss herein the possible mechanisms and the significance of mToR blockade-induced proteinuria.     

Sirolimus-associated diffuse alveolar hemorrhage in a renal transplant recipient on long-term anticoagulation

Sirolimus (rapamycin, rapamune) is an effective immunosuppressant that has been widely used in solid organ transplantation. Recently, two disconcerting side effects, namely pulmonary toxicity, usually in the form of interstitial pneumonitis, and the onset of nephrotic range proteinuria, have been recognized. We report the case of a renal transplant recipient who had been on chronic anticoagulation therapy for a mechanical aortic valve, and who developed pulmonary distress necessitating emergent intubation 18 days after starting sirolimus therapy. Open lung biopsy showed diffuse alveolar hemorrhage with fibrin deposits in the alveolar spaces and small bronchi. Urine protein/creatinine ratio at that time was 16.7. Upon discontinuation of sirolimus, alveolar hemorrhage and nephrotic range proteinuria resolved. We suggest that extra vigilance be paid in individuals who are on chronic anticoagulation and who are started on sirolimus.     

Proteinuria Developing After Clinical Islet Transplantation Resolves with Sirolimus Withdrawal and Increased Tacrolimus Dosing

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.     

Sirolimus conversion experience in a single center

OBJECTIVE: One major cause of graft loss is chronic allograft nephropathy (CAN), which may relate to calcineurin inhibitors (CNIs). We converted CAN cases from CNIs to sirolimus and observed the outcomes. METHOD: From January 2004 to August 2007, there were 28 kidney recipients in our center with creeping creatinine levels compatible with CAN. We started sirolimus at 2 mg/d and reduced the CNIs gradually. Sirolimus trough levels were kept between 5 and 8 ng/mL. Mycophenolic acid was cut in half; there was no adjustment on prednisolone dose. RESULTS: The mean switch time was 47.3 months after transplantation. One case discontinued sirolimus due to severe drug-induced pneumonitis. Twelve of the 27 (45%) patients showed improvements in graft function. The most frequent complications were anemia (13/28), hyperlipidemia (13/28), and pneumonitis (4/28). A baseline serum creatinine level less than 2.2 mg/dL seemed to forecast a response to sirolimus conversion. Most of the graft functional improvement occurred within 6 months after the switch. No graft or patient loss was encountered. CONCLUSION: Our experience suggested that 45% of patients with sirolimus conversion showed improved graft function. Among patients within 1 year after transplantation, those with a creatinine level less than 2.2 mg/dL, no proteinuria, and no hyperlipidemia seemed to be better candidates for Sirolimus conversion.     

Reduction of Slit Diaphragm-associated Molecules by Sirolimus: Is it Enough to Induce Proteinuria?

Sirolimus (SRL), a mammalian target of rapamycin inhibitor, is widely used in transplantation, but the mechanisms whereby it induces adverse effects, such as proteinuria and edema, remain unclear. To determine whether isolated SRL induces proteinuria or not, the authors intraperitoneally injected C57BL/6 mice with different doses of SRL (0 mg/[kg·d], 3 mg/[kg·d], 10 mg/[kg·d], or 30 mg/[kg·d]) for 24 days. Urinary albumin excretion was then quantified using a double-sandwich enzyme-linked immunosorbent assay, and serum creatinine levels were measured using a single dry-film chemistry auto-analyzer. The mRNA expression levels of various genes were also measured by polymerase chain reaction. Urinary albumin was not detected in the SRL-treated mice, but serum creatinine levels were found to increase dose-dependently and were significantly higher in the animals treated with 30 mg/kg of SRL than in untreated controls. Glomerular mRNA expression profiling showed down-regulations of podocyte-related genes (Wilms tumor 1, synaptopodin, nephrin, CD2-associated protein, and podocin) and of transforming growth factor-beta (a marker of fibrosis) in sirolimus-treated mice. In addition, expressions of the antiapoptotic genes Bcl-2 and Bcl-xL were also down-regulated. Furthermore, the protein levels of these genes in mice kidney were also decreased by sirolimus. Although sirolimus treatment reduced the expressions of slit diaphragm–associated molecules and increased serum creatinine levels, it failed to induce proteinuria. Our findings indicate that proteinuria is not induced by isolated SRL treatment. Further studies are required to identify conditions in which sirolimus induces proteinuria.     

Unusual post-transplantation recurrence of focal segmental glomerulosclerosis which resolved with cyclosporine but not with sirolimus

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) is frequent after the first kidney transplantation (KT), but a recurrence that only occurred after the second KT has never been reported. Although cyclosporine reduces proteinuria and prolongs graft survival in patients with recurrent glomerulosclerosis, the effectiveness of sirolimus for this condition is still not known. We report, for the first time as far as we know, the case of a 35-year-old black male patient who experienced a recurrence of FSGS, 10 days after a second KT, although no recurrence had occurred after the first. Cyclosporine treatment led to a decrease in proteinuria, whereas mycophenolate mofetil and angiotensin-converting enzyme inhibitor had no effect. Cyclosporine was replaced by sirolimus as treatment for chronic allograft nephropathy 24 months after KT. Nephrotic syndrome, which reappeared 3 weeks after the switch, was cured by cyclosporine re-introduction. The absence of FSGS recurrence after the first graft does not totally preclude its recurrence after the second. This observation points to the effectiveness of cyclosporine for the recurrence of FSGS and indicates that sirolimus should be given with caution in such cases.     

Proteinuria following conversion from azathioprine to sirolimus in renal transplant recipients

Recent studies have reported a significant increase of proteinuria in kidney transplant recipients who were switched from a calcineurin inhibitor (CI) to sirolimus. This has (partly) been ascribed to the hemodynamic renal effects of CI withdrawal. We have evaluated the evolution of proteinuria in renal transplant recipients who underwent conversion from azathioprine to sirolimus. In a randomized, prospective, multicenter study called RESCUE (Recurrent cutanEous Squamous cell Carcinoma Under RapamunE) the efficacy and safety is investigated of conversion to sirolimus in stable renal transplant recipients with a cutaneus squamous cell carcinoma (SCC). In our center 25 patients have been included in this study of which 13 patients were randomized to continue their current immunosuppressive treatment and 12 to conversion to sirolimus. After a mean follow-up of 360 days mean proteinuria increased from 0.37+/-0.34 to 1.81+/-1.73 g/24 h after conversion to sirolimus (P<0.005). In the control group there was no change in proteinuria. A significant increase of proteinuria was observed in all seven patients with proteinuria before conversion, whereas proteinuria remained absent in all patients without previous proteinuria. Two of the patients with proteinuria were converted from cyclosporine and five were converted from azathioprine to sirolimus. Sirolimus was discontinued in five patients with proteinuria, and in all of them proteinuria declined to baseline values. Our study demonstrates that conversion from azathioprine to sirolimus after kidney transplantation may cause a reversible increase of proteinuria. Sirolimus-induced proteinuria therefore cannot be ascribed to the hemodynamic renal effects of withdrawal of CI.     

Azoospermia in a renal transplant recipient during sirolimus (rapamycin) treatment

Sirolimus is used as a powerful immunosuppressant drug in patients after organ transplantation. It was shown to block spermatogenesis by interrupting the stem cell factor/c-kit system. Oligozoospermia was shown in single patients. In addition, a decrease of testosterone and an increase of gonadotropin levels were observed. We report on a young patient who showed azoospermia during the treatment with sirolimus after renal transplantation. After changing the immunosuppression to tacrolimus, spermatogenesis of the patient recovered. Five months after cessation of the treatment with sirolimus, a sperm concentration of 8 x 10(6) ml(-1) was found. Depression of spermatogenesis is an important side effect in younger men who aspire paternity, so that waiving of sirolimus is advisable in these patients.     

Early experience with conversion to sirolimus in a pediatric renal transplant population

Sirolimus is an immunosuppressive agent that offers potentially significant benefits for young transplant patients facing life-long treatment. Its action of reducing cell proliferation may reduce the risk of chronic allograft nephropathy and posttransplant neoplasia. Twenty-nine children were converted from calcineurin inhibitors to sirolimus after renal transplantation and followed for a minimum of 12 months. Glomerular filtration increased transiently in those converted before 12 months after transplantation but not in those converted later, when chronic histological changes had developed. Mild acute rejection occurred after conversion in 10%, and side effects led to cessation of sirolimus in 31%. Anemia occurred in 55% of patients and responded well to darbepoetin. Most side effects (anemia, hypercholesterolemia, mouth ulcers, and myalgias) became less severe with time. The number of antihypertensive drugs required decreased significantly on sirolimus. Although side effects are frequent on sirolimus, in the majority of children, they are mild enough to allow the patient to continue taking the drug, and for these children the long-term benefits are potentially valuable.     

Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerular sclerosis after renal transplantation

Proteinuria and nephrotic syndrome due to recurrent disease may develop after renal transplant in patients with focal glomerular sclerosis (FGS). The rapid onset of proteinuria in many of these patients suggests a possible humoral mediator. We studied serum from a patient who has had recurrence of nephrotic syndrome and FGS after two cadaveric renal allografts to determine if a serum factor capable of producing increased urinary protein excretion was present. Serum was infused into the aorta of anesthetized rats. During infusion of serum from the patient with recurrent FGS, there were significant increases in mean urinary protein and rat albumin excretion which persisted after infusion. When sera from ten patients with nephrotic syndrome secondary to other glomerulopathies were infused no changes in urinary protein or albumin excretion were noted. Likewise no changes in urine protein or albumin excretion were produced with infusion of serum from a patient with FGS without recurrence after transplantation. Increases in urine protein and albumin excretion noted during and after infusion of recurrent FGS serum were independent of changes in glomerular filtration rate, urine volume, or fractional excretion of sodium. These results suggest there is a factor or factors present in the serum of this patient capable of producing enhanced urinary protein excretion in the rat. This factor(s) which is heat stable at 56 degrees C could possibly play a role in the pathogenesis of recurrent nephrotic syndrome.     

Proteinuria after conversion to sirolimus in kidney transplant recipients: impact of pre‐existing proteinuria,graft function,and angiotensin‐converting enzyme inhibitors/angiotensin‐receptor antagonists

Marx C, Busch M, Ott U, Gerth J, Wolf G. Proteinuria after conversion to sirolimus in kidney transplant recipients: impact of pre‐existing proteinuria, graft function, and angiotensin‐converting enzyme inhibitors/angiotensin‐receptor antagonists.
Clin Transplant 2009 DOI:10.1111/j.1399‐0012.2009.01142.x.
© 2009 John Wiley & Sons A/S. Abstract: Background: Proteinuria is a known side effect of therapy with sirolimus. The effect of angiotensin‐converting enzyme inhibitors or angiotensin‐receptor blockers (ACEI/ARB ) on sirolimus‐associated proteinuria has not yet been assessed. Patients and methods: A retrospective cohort study of renal transplant patients treated with sirolimus (n = 55) was performed. Results: Of 55 patients, 24 (44%) had no proteinuria (<0.15 g/d) prior to conversion. Of 24 patients, 11 (46%) showed de novo proteinuria >0.15 g/d after 12 months, only 2 developed proteinuria > 1 g/d. The total number of proteinuria >1 g/d after 12 months including patients with pre‐existing proteinuria >1 g/d (n = 3) was seven of 55 patients (13%). Multivariate regression analysis revealed pre‐existing proteinuria > 0.15 g/d and reduced glomerular filtration rate as independent predictors for the development of proteinuria after conversion to sirolimus. Conclusion: Reduced glomerular filtration rate and pre‐existing proteinuria but not therapy with ACEI/ARB are independent predictors for proteinuria after conversion to sirolimus. Treatment with ACEI/ARB did not reduce pre‐existing proteinuria after conversion except in single cases with severe proteinuria.     

Sirolimus therapy may cause cardiac tamponade

The side‐effects associated with the immunosuppressive drug sirolimus are numerous and constitute a major limitation for its use in renal transplantation. In this study, we describe two cases of renal transplant recipients treated with sirolimus who developed pericardial tamponade associated with interstitial pneumonia, proteinuria, microcytic anemia and, in one case, lymphocytic meningitidis. An extensive search for infectious agents was negative, and all symptoms disappeared after sirolimus interruption. Therefore, this case demonstrates for the first time that sirolimus can cause pericardial tamponade as well as lymphocytic meningitidis.     

Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue

BACKGROUND: Little is known about the incidence and evolution of proteinuria as a complication of sirolimus rescue in children. This study describes pediatric renal transplant (Tx) recipients who were treated with sirolimus and who developed heavy proteinuria. Risk factors for the development of proteinuria and its time course are explored. METHODS: Data at various time points after sirolimus introduction were abstracted from the records of children treated at the author's center. The repeated measures general linear model and the Student's paired t test were used to analyze changes in laboratory values over time. RESULTS: Of the 13 children on sirolimus, 12 developed heavy proteinuria after a mean interval of 1 month. The mean urine protein (Up)-to-creatinine (c) ratio increased from 1.1 to a peak value of 3.9 (P=0.003) at 4.6 months after the start of sirolimus. Although not statistically significant, children on no calcineurin inhibitor (CNI) had a greater increase in the Up/c than those on low-dose CNI. At last follow-up, with the use of angiotensin receptor blockers (ARB), the Up/c declined to 2.2. No predictors could be identified for the development of proteinuria. CONCLUSIONS: Heavy proteinuria is common after the use of sirolimus as rescue therapy in children with renal Tx. Whether this is attributable to a toxic effect of the sirolimus itself or to lower CNI exposure is uncertain. Early detection of proteinuria is important to enable prompt intervention. Most children have a reduction in their Up/c with the use of ARB and can therefore be continued on sirolimus.     

Chylous ascites in a renal transplant recipient under sirolimus (rapamycin) treatment

Ascites is a rare complication of renal transplantation. Ascites has been reported after kidney transplantation due to rejection, decapsulation of the graft, urinary or vascular leak, lymphocele, transudation, or infection. While technical complications of the procedure are the most frequent cause, portal hypertension and graft rejection are other causes. Ascites can occur after renal transplantation independent of kidney function. Usually, a time relation can be made between the surgical procedure and ascites development. Chylous ascites is still more uncommon; it is usually related to traumatic lymphatic injury. Drugs are rarely associated with the genesis of ascites. Sirolimus has been associated with a high rate of lymphoceles, lymphedema, and pulmonary alveolar proteinosis. The exact mechanisms remain unknown. The risk for lymphocele formation with sirolimus is 12% to 15%. Ascites is an adverse effect with an incidence between 3% and 20%, but no relation between sirolimus and chylous ascites was previously established. We present a clinical report of chylous ascites in a renal transplant patient under sirolimus therapy; our investigation pointed to sirolimus as the cause.     

Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass

Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P < 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.     

Sirolimus-associated acute respiratory distress syndrome in a renal transplant recipient

Sirolimus is a new potent immunosuppressive drug used in organ transplantation; its major advantage is the absence of deterioration in renal function. Documented adverse effects include myelosuppression and hyperlipidemia. Recently several cases of sirolimus-associated interstitial pneumonitis have been reported, usually of mild severity. We report a new case that was complicated by a severe acute respiratory distress syndrome, which required several days of mechanical ventilation. No infectious or cardiogenic etiology was documented. Low sirolimus blood levels and acute CD4 lymphocytic alveolitis suggested an immune-related mechanism rather than a direct toxic effect of the drug. The patient recovered after discontinuation of sirolimus and the administration of corticosteroids.     

Generalized, pruritic, ulcerating maculopapular rash necessitating cessation of sirolimus in a liver transplantation patient.

The use of sirolimus as an alternative to calcineurin antagonists has enabled the continuation of immunosuppression in patients with renal impairment with preservation of kidney function. Sirolimus is generally well tolerated, with the main causes of cessation of therapy related to its effect on blood lipid profile as well as leukopenia and thrombocytopenia. We report a case of a debilitating ulcerating maculopapular rash necessitating cessation of the drug in a liver transplantation patient. A 56-year-old Caucasian liver transplantation patient presented with a diffuse, debilitating rash attributed to sirolimus use. This ultimately necessitated cessation of the immunosuppressant with subsequent resolution of her symptoms. From a review of the current literature, this is a highly unusual adverse reaction to sirolimus.