Post-operative complications of tibial plateau fractures treated with screws or hybrid external fixation.

PURPOSE: To assess the complications and second surgeries rates at 1 year follow-up in a group of patients underwent minimally invasive fixation with screws or hybrid external fixation (HEF) for tibial plateau fractures (TPF). The hypothesis was that low Schatzker (I-IV) TPF would have shown a lower complication rate with respect to high Schatzker (V-VI) TPF. METHODS: 148 patients who underwent minimally invasive surgery with screws or HEF for TPF were included and pooled in two groups: mono-condylar (Schatzker I-IV) and bi-condylar (Schatzker V-VI). The rate of second surgeries and complications, such as stiffness, infection, wound dehiscence and malunion occurred within 1 year, were reported. RESULTS: Statistically significant difference between mono-condylar and bi-condylar groups was found in terms of stiffness (18% vs. 37%, p = 0.01), malunion (4% vs 21%, p = 0.004) and second surgeries (32% vs. 48%, p = 0.049). Associated procedures performed during TPF fixation increased risk of second surgeries (OR 2.1, p < 0.001). No differences in terms of second surgeries and complications were found in bi-condylar group treated with screws and HEF. CONCLUSION: Bi-condylar TPF treated with minimally invasive surgery developed a significantly higher rates of stiffness, malunion and second surgeries within 1 year compared to mono-condylar fractures. Moreover, when an associated procedure was performed, the risk of a reoperation was nearly doubled. Trial registration number PG 0012506 CE AVEC 620/2018/Oss/IOR.

Migration of the femoral component and clinical outcomes after total knee replacement: a narrative review.

Loosening is considered as a main cause of implant failure in total knee replacement (TKR). Among the predictive signs of loosening, migration is the most investigated quantitative parameter. Several studies focused on the migration of the tibial component in TKR, while no reviews have been focused on the migration of the femoral component and its influence on patients' clinical outcomes. The aim of this narrative review was (1) to provide information about of the influence of migration in femoral component of TKR prostheses, (2) to assess how migration may affect patient clinical outcomes and (3) to present alternative solution to the standard cobalt-chrome prostheses. A database search was performed on PubMed Central® according to the PRISMA guidelines for studies about Cobalt-Chrome femoral component migration in people that underwent primary TKR published until May 2020. Overall, 18 articles matched the selection criteria and were included in the study. Few studies investigated the femoral component through the migration, and no clear migration causes emerged. The Roentgen Stereophotogrammetric Analysis has been mostly used to assess the migration for prognostic predictions. An annual migration of 0.10 mm seems compatible with good long-term performance and good clinical and functional outcomes. An alternative solution to cobalt-chrome prostheses is represented by femoral component in PEEK material, although no clinical evaluations have been carried out on humans yet. Further studies are needed to investigate the migration of the femoral component in relation to clinical outcomes and material used.

Two different posterior-stabilized mobile-bearing TKA designs: navigator evaluation of intraoperative kinematic differences.

PURPOSE: The purpose of this study was to compare two types of posterior-stabilized (PS) mobile-bearing (MB) total knee arthroplasties (TKAs). The hypothesis was that no major differences were going to be found among the two TKA designs. METHODS: Two cohorts of patients who were divided according to implant design (Cohort A, new design gradually reducing radius PS MB TKA; Cohort B, traditional dual-radius PS MB TKA) were analyzed by means of intraoperative navigation. All operations were guided by a non-image-based navigation system that recorded relative femoral and tibial positions in native and implanted knees during the following kinematic tests: passive range of motion (PROM), varus-valgus stress test at 0° and 30° (VV0, VV30) and anterior/posterior drawer test at 90° of flexion (AP90). RESULTS: There were no significative differences in kinematic tests between the two implants. Cohort A, however, showed a different post-implant trend for VV0 and VV30 that were lower than the pre-implant ones, as expected, while for Cohort B, the trend is opposite. However, the gradually reducing radius prosthesis (Cohort A) showed a trend of improving stability (29% compared to the preoperative status) in mid-flexion (VV30) which the traditional dual-radius design (Cohort B) would not. Moreover, we found no differences among postoperative results of the two TKA designs. CONCLUSION: Despite design variations, no difference has been found among the prostheses in terms of PROM, rotations and translations. Both design kinematics did not show paradoxical external rotations, but an increase in femoral translation in mid-flexion without affecting the functioning of the prosthesis. LEVEL OF EVIDENCE: II.

Taking Care of Relationships in the Intensive Care Unit: Positive Impact on Family Consent for Organ Donation.

BACKGROUND: Organ donation refusal from relatives of potential donors with brain death significantly reduces organ availability. The need for organ donation has increased over time, but the shortage of available donors is the major limiting factor in transplantation. We analyzed the impact of a new systematic communication approach between medical staff and patients' relatives on the rate of consent to organ donation. METHODS: The study was conducted as a single-center, non-randomized, controlled, before-and-after study at an 18-bed intensive care unit (ICU) of a university hospital. We compared the rate of consent for organ donation before and after the introduction of the new communication approach. RESULTS: A total of 291 brain-dead patients were studied. The consent rate increased from 71% in the pre-intervention period (2007-2012) to 78.4% in the post-intervention period (2013-2015), with an 82.75% increase in the 2014 to 2015 period. During these periods, no significant variation of consent to organ donation was recorded at the national and regional levels. CONCLUSIONS: The introduction of a new communication approach between medical staff and relatives of brain-dead patients was associated with a significant increase in the rate of consent to donation. Our results highlight the importance of empathy with relatives in the ICU.

[Proteomics and the kidney: an innovative approach to the study of renal disease]. / Proteomica e rene: un approccio innovativo allo studio delle malattie renali.

In the post human genome era, several ''omics'' fields are emerging. Proteomics has experienced a rapid growth in the recent past and has great potential for the future. Proteomic technologies are used with increasing frequency also in nephrology. The aim of this review is to examine the recent application of emerging proteomic technologies to the study of renal physiology and pathophysiology. We highlight the use in renal research of a number of available techniques including 2-dimensional gel electrophoresis, liquid chromatography/mass spectrometry, surface-enhanced laser desorption/ionization, and capillary electrophoresis/mass spectrometry. We examine the role, efficacy and diagnostic potential of the different proteomic approaches, focusing on current difficulties and potential solutions. The integrating role of bioinformatics and the need for standardized procedures for sample preservation and analysis and reporting of results are also discussed. Although the field is still in an embryonic stage, the knowledge gained up to now is important not only for a better understanding of renal physiology and pathophysiology, but also for the identification of disease markers and the development and follow-up of new therapies. This review gives an overview of proteomics, providing background information, outlining the scopes, highlighting the applications in nephrology, and reporting advantages and limitations.

Two- and four-dimensional echocardiography with B-flow imaging and spatiotemporal image correlation in prenatal diagnosis of isolated total anomalous pulmonary venous connection.

OBJECTIVES: To explore whether the use of four dimensional (4D) ultrasound examination with B-flow imaging and spatiotemporal image correlation (STIC) can supply additional information with respect to two-dimensional (2D) gray-scale and color Doppler echocardiography in the prenatal characterization of isolated total anomalous pulmonary venous connection (TAPVC). METHODS: The study population comprised a group of three TAPVC fetuses that had been examined exclusively by conventional echocardiography, and a group of four additional cases initially identified by conventional echocardiography and examined further by 4D ultrasonography; a thorough postnatal work-up was available for all fetuses. RESULTS: At our center, isolated TAPVC was found in seven of 1040 fetuses with cardiac defects (0.67%). Anomalous drainage was supracardiac to the innominate vein in three cases, cardiac to the coronary sinus in two, and infracardiac to the portal vein in the remaining two cases. An evident asymmetry between left heart and right heart structures was observed in 4/7 cases. The confluence of the anomalous pulmonary veins (PVs) was visualized in 4/7 cases and the connecting vertical vein was identified in 3/5 cases at 2D echocardiography. 4D ultrasound imaging with B-flow imaging and STIC clearly visualized the anomalous PV confluence and the draining vertical vein in all four cases examined. CONCLUSION: 2D and color Doppler echocardiography appears to diagnose reliably TAPVC, albeit with some limitations in thorough assessment of the pathology, depending on the anatomy of the defect, on the technical adequacy of the equipment used and on the experience of the operator. 4D ultrasound examination with B-flow imaging and STIC is apparently able to facilitate identification of the anatomical features of TAPVC, thus supplying additional information over that provided by 2D fetal sonography.

Novel application of 4D sonography with B-flow imaging and spatio-temporal image correlation (STIC) in the assessment of the anatomy of pulmonary arteries in fetuses with pulmonary atresia and ventricular septal defect.

OBJECTIVES: To assess the reliability of two-dimensional gray-scale (2D) and color Doppler echocardiography in the study of the size and anatomy of the central pulmonary arteries and of the sources of pulmonary blood flow in a case series of fetuses with pulmonary atresia and ventricular septal defect (PA-VSD), and to evaluate whether the use of 4D ultrasound with B-flow imaging and spatio-temporal image correlation (STIC) can improve prenatal diagnostic accuracy. METHODS: The study population comprised a group of seven PA-VSD fetuses that had been examined by 2D and color Doppler echocardiography exclusively, and a group of five additional cases identified initially by conventional echocardiography and examined further by 4D ultrasound, for all of which a thorough postnatal or autopsy study of the size and anatomy of the pulmonary arteries and blood supply was available. RESULTS: 2D and color Doppler echocardiography failed to assess the anatomy of the central pulmonary arteries and the source of the pulmonary blood supply in 33% and 25% of the 12 cases, respectively. 4D ultrasound with B-flow imaging and STIC assessed successfully the anatomy of the pulmonary arteries and the source of pulmonary blood supply in all five fetuses examined. CONCLUSIONS: The prognosis of PA-VSD is influenced by the anatomy of the pulmonary arteries and the sources of the pulmonary blood supply, and by coexisting extracardiac and genetic anomalies. Our findings, although limited to a small sample size, suggest that 4D echocardiography with B-flow imaging and STIC, unlike 2D ultrasound, can provide thorough visualization of very small vessels and of the arterial blood supply to the lungs of fetuses with PA-VSD. 4D ultrasound may be used in the future to improve and help to detail the diagnosis of other fetal cardiac defects.

A study on glucose metabolism in a small cohort of children and adolescents with kidney transplant.

Post-transplant diabetes mellitus (PTDM) and impaired glucose tolerance are now considered among the major adverse events following organ transplantation. The present study was aimed at investigating the regulation of glucose metabolism in pediatric recipients of a kidney transplant (KT), receiving tacrolimus or cyclosporine A-based immunosuppression. Twelve subjects, eight males and four females, aged 12.1+/-3.8 yr, and with a mean time from KT of 45.6 months were enrolled in the study. All patients had a basal evaluation of fasting glucose (GF), fasting insulin (IF), C-peptide and glycated hemoglobin (HbA1c) levels. They then underwent oral glucose tolerance test (OGTT), with measurement of blood glucose and insulin concentration. Two children had impaired GF, associated with supernormal HbA1c levels, one patient showed impaired glucose tolerance, none had PTDM. Peripheral insulin resistance, as measured by quantitative insulin sensitivity check index (QUICKI) and homeostasis model assessment estimate of insulin sensitivity (HOMA-IR) index, was enhanced in 3 patients. Subsequently, GF significantly increased with time from transplant (p=0.01), while fasting C-peptide and the area under the curve of insulin correlated with creatinine clearance. In conclusion, our results, although generated in a small sample size, would suggest that long-term follow-up of children receiving a KT should extend to explore the response to oral glucose load and at least the basal measure of insulin response.

Double J stent with antireflux device in the prevention of short-term urological complications after cadaveric kidney transplantation: single-center prospective randomized study.

The placement of a double J stent to protect a uretero-vesical anastomosis in a kidney transplant is a widespread procedure performed to reduce the incidence of fistula and stenosis at the anastomosis. However, the presence of a double J stent may cause vesicoureteral reflux (VUR), predisposing one to urinary tract infections (UTIs), which may be a significant source of morbidity for the graft. We evaluated whether a ureteral stent incorporating an antireflux device can reduce the incidence of ureteral reflux and UTIs. From January to December 2003, 44 kidney transplant recipients were randomized to receive a 14-cm 4.8-F double J stent with (group A) or without an anti-reflux device (group B). Primary end points were the reduction of the incidence of VUR and of UTIs. The secondary end point was the graft function, on the basis of mean serum creatinine level at 3, 6, and 12 months. We failed to observe statistically significant differences in terms of either the incidence of VUR and UTIs, or the short-term outcomes of the grafts. We concluded that the anti-reflux device does not have an impact on the incidence of stent-related side effects.

[Identification of an objective reference parameter for the reconstruction of a large incisional hernia following physiological principles]. / Identificazione di un parametro obiettivo di riferimento per la ricostruzione secondo criteri fisiologici del grande laparocele.

Repairing a parietal defect of a large incisional hernia should not be limited to the closure of the breach by means of the modern biocompatible prosthetic sheets, but must also be able to restore a correct intra abdominal pressure, otherwise the derangement from the normal respiratory dynamics and the circulatory stasis in the abdominal veins and in those of the lower limbs remain unaltered. Over-correcting the parietal abdominal tension on the contrary can cause a dangerous compartmental syndrome. The attempts of an intraoperative measurement of the correct intra abdominal pressure restoration has been generally hampered from the condition of curarization of the patient during the operation. Using the automatic mechanical ventilator fixed at volume and not at pressure priority, as usual, can offer the possibility to calibrate, following objective parameters, the propriety of the surgical repair still during the final phases of the reparative operation. The simplicity and ingenuity of the here proposed method and the normal availability in every operative theatre of the necessary means for this measurements described, requires attention among the surgeons and a large diffusions of its simple use.

[Cardiovascular risk and renal transplantation]. / Il rischio cardiovascolare nel paziente con trapianto renale.

Cardiovascular disease after renal transplantation is often the expression of a disease process that first started with the onset of renal dysfunction many years before, and its prevention starts with the early predialysis phase of chronic renal failure and with the aggressive treatment of hypertension and dyslipidemia. The evidence that dialysis treatment itself accelerates arterial damage is poor. After transplantation, however, many patients are restored to a state not of normal renal function but of chronic renal impairment and have drug-induced hypertension and dyslipidemia, resulting in a vastly increased risk of atherosclerosis. Further research is required on optimal strategies to prevent or ameliorate cardiovascular disease, to establish the roles of lipid-lowering and antihypertensive therapies after transplantation and to define immunosuppressive ad hoc treatments for each kind of patient.

[Experimental study of the effect of the Argon Beam Coagulator on organic tissues from the viewpoint of surgical utilization]. / Studio sperimentale dell'effetto dell'Argon Beam Coagulator su tessuti organici in vista dell'impiego in chirurgia.

The Argon Beam Coagulator has gained his space in surgery thanks to its operative characteristics, that are very useful in sealing the bleeding parenchymal tissue with minimal injury to the surroundings. The aim of the present study is that of evaluate the physical properties of the instrument in its coagulation action. The experimental study with the Birtcher 6000 Argon Beam Coagulator has been designed to measure the top temperature that develops right where the Argon beam meets the tissue, while operating. Using a laser guided telethermometer, the searching of that temperature was uneasy right on the operatory field because of the unwilling movements of the operator hand and those of the patient himself. Therefore a similar protocol was made on a piece of meat coming from the butcher. At the longest application of the beam coagulation on the same point the developed temperature was never higher than 100 degrees C whilst a complete coagulation effects. The advantage of the Argon Beam coagulation are therefore to seal the diffuse bleeding without injury to this adjacent tissues, never exposed to a temperature higher than that of boiling water. The advantages are also evident in comparison with the more usual spray electrosurgery that is instead characterized by a wide carbonisation also with this spray option.

Rare phenotype and transplantability in cadaveric kidney transplant.

The waiting list for kidney transplants in the Apulia region contains recipients (about 30%) who were never selected for transplant due to the rare HLA antigen phenotypes and homozygosis. Therefore, an algorithm was selected to equilibrate the chance for patients to be selected despite a rare phenotype. We calculated for each patient, the sum (%) of the A, B, DR antigen frequency (total phenotypic frequency; TPF). All the potential recipients were grouped into five classes in increasing order of TPF. The number transplanted depended on the phenotype frequency. The selection index was the quotient of the number selected and the total number of patients. The selection index was 0.28 to 0.43 to 0.79 to 1.34 to 2.38 from class 1 to 5. To equilibrate the transplantability of rare phenotype recipients on the waiting list, a bonus was introduced for the most disadvantageous frequency class. Adding the bonus modified the selection index as follows: 1.0 to 1.25 to 1.5 to 1.34 to 2.38, which appears more equilibrated except for the class 5. In conclusion, if a bonus is applied for rare phenotypes, the chance to be transplanted becomes similar between patients with other parameters the same.

Experience with cyclosporine: approaching the therapeutic window for C2 levels in maintenance kidney transplant recipients.

This study was aimed to evaluate the clinical benefit of C2 monitoring in 191 stable renal transplant patients previously monitored by C0. All patients had been transplanted for at least 1 year and received cyclosporine (CsA)-based immunosuppression since the start. At the inceptions C0 levels were significantly correlated with C2 values (P<.0001). Patients with starting C2 levels >1000 ng/mL showed significantly higher levels of serum creatinine (sCr) both at inception (1.66 +/- 0.50 vs 1.44 +/- 0.41 mg/dL; P=.0021) and at the end of a 2-year follow-up (1.84 +/- 0.80 vs 1.46 +/- 0.51 mg/dL; P=.005). C2 monitoring revealed that a high percentage of patients were overexposed to CsA, mainly in the subgroup with most recent renal engraftments (12 to 24 months). The switch to C2 monitoring was associated with a slower deterioration of graft function (P=.02). Further, the mean values of C2 over a 2-year follow-up were inversely correlated with sCr at the end of follow-up (P=.0005). Finally, patients with mean threshold C2 levels above 720 ng/mL, roughly corresponding to the median value of C2, showed significantly lower levels of sCr at the end of follow-up (P=.0004). In conclusion, C2 monitoring of maintenance renal transplant patients allows one to identify a significant percentage of overexposed subjects, possibly limiting the rate of progression of chronic graft dysfunction. Target range values between 700 and 900 ng/mL appear to be associated with better long-term kidney graft function.

[Recurrent and de novo glomerular disease after renal transplantation]. / Recidive della nefropatia di base e nefropatie "de novo" in pazienti portatori di trapianto renale.

The development and progression or recurrent and de novo renal disease does not seem to have been influenced by the use of newer immunosuppressive agents. The rate of development of recurrent and de novo renal disease has been variable and is perhaps related to pre-existing immunological and/or haematological factors. The diagnosis of recurrent glomerulonephritis requires an accurate diagnosis of both primary renal disease and subsequent disease in the transplant kidney. Published data suggest that recurrent glomerulonephritis occurs in 6 to 19.4% of all renal transplant recipients, and causes the loss of 1.1 to 4.4% of all renal allografts. However, the propensity for glomerulonephritis to recur seems to be time dependent. Consequently, as grafts survival increases, so, too, does the likelihood of disease recurrence. In conclusion, currently available data on recurrence patterns of the less common nephropathies are unfortunately inadequate and our practice is therefore guided by small series, case reports, and local experience. It is to be hoped for that this deficit be addressed in the near future through the use of powerful database and registries, some of which are prospectively collecting data on specific disorders. Prospective studies on the treatment of recurrent glomerulonephritis are lacking. As grafts last longer and recurrent glomerulonephritis becomes a more significant entity, affecting greater numbers of patients, the opportunity to study management prospectively will be possible. This will probably require a cooperative, multicentre approach but it is clearly the only way forward, remembering that renal transplantation is a treatment, not a cure.

[Double renal transplant. Retrospective analysis of data on the patient population with double kidney transplantation in the setting of the AIRT]. / Trapianto di rene doppio. Analisi retrospettiva dei dati relativi alla popolazione dei pazienti portatori di trapianto renale doppio in ambito AIRT.

BACKGROUND: The number of patients on the waiting list for renal transplantation has progressively increased in the last decade, while the number of potential donors have remained the same. The expansion of the donor pool using marginal donors may represent a possible, although partial solution to this problem. Thus, the aim of the present analysis was to evaluate the graft survival of double renal transplant from marginal donors performed within the Associazione InterRegionale Trapianti (AIRT) and to assess whether this procedure is characterized by an increase in surgical complications. PATIENTS: 79 double renal transplants were performed from January 1st 1999 to December 31st 2002 in three AIRT transplant centers (Bari, Bologna, Torino). Immunosuppressive therapy for all patients included anti-IL-2 receptor antibodies, corticosteroids, tacrolimus and mofetil micophenolate. RESULTS: Graft survival was 90% at 36 months. Acute rejection incidence was 6.4%, while the incidence of surgical complications was 16.6%. CONCLUSIONS: The present study opens new perspectives to overcome the actual shortage of donor kidneys. Indeed, the use of marginal organs for double renal transplantation not suitable for single transplantation may create an additional pool of potential donors and significantly increase the number of kidney transplants.

[HCV+ patients on the waiting list for kidney transplantation. Retrospective analysis of data on the patient population with hepatitis C on the waiting list for kidney transplantation in the setting of the AIRT]. / Pazienti HCV+ in lista d'attesa per trapianto renale. Analisi retrospettiva dei dati relativi alla popolazione dei pazienti affetti da epatite C in lista d'attesa per trapianto di rene in ambito AIRT.

BACKGROUND: HCV infection in hemodialysis is still a matter of debate from an epidemiological and clinical point of view. Evaluation criteria for HCV-infected patients as transplant candidates are still not adequately standardized. Aims of the present study were to investigate: 1. the percentage of HCV positive patients on the waiting list of three Italian regions belonging to the Associazione InterRegionale Trapianti (AIRT); 2. to analyze the clinical approach in the evaluation of these patients in the attempt to define national guidelines for their pre- and post-transplant management. PATIENTS: We evaluated 2045 uremic patients on the waiting lists of four transplant centers (Bari, Bologna, Modena, Novara) belonging to AIRT at 31/12/2002. RESULTS: The overall prevalence of HCV positive patients was 14.2%, with a peak in the Puglia waiting list. The most common screening tests were AST and ALT serum levels and viral load (HCV RNA). Although there is a clear evidence that histological parameters are the main diagnostic and prognostic markers, a liver biopsy was performed in only 9.5% of patients. An even smaller percentage of HCV-infected patients underwent anti-viral therapy. CONCLUSIONS: Our retrospective analysis evidenced the need to improve common clinical strategies in approaching HCV-infected canditates to renal transplantation in the attempt to improve their post-transplant outcome.

[Malignant neoplasia and kidney transplantation. Retrospective analysis of data on the population having kidney transplantation with de novo neoplasia in the setting of the AIRT]. / Trapianto renale e neoplasie. Analisi retrospettiva dei dati relativi alla popolazione dei trapiantati di rene affetti da neoplasie de novo in ambito AIRT.

BACKGROUND: In transplanted patients undergoing immunossuppressive therapy the incidence of malignant neoplasia is 3-4 times higher than in the general population. Aim of the present study was to evaluate the prevalence of different tumours and the links between modulation of immunosuppressive therapy and patient and graft survival. PATIENTS: We evaluated 2029 kidney-transplanted patients from four Transplant Centres (Bari, Bologna, Modena, Novara) belonging to the Associazione InterRegionale Trapianti (AIRT). RESULTS: The incidence of neoplastic disease after transplantation was 3.9% in our population with a median time between transplantation and clinical onset of 23 months. We demonstrated a significant difference in the geographical distribution of different tumours. We did not observe any correlation with specific immunosuppressive drugs. Finally, dramatic reduction of the immunosuppression levels did not modify either the patients' or the graft's survival. CONCLUSIONS: Several factors can influence the post-transplant onset of neoplastic diseases with immunosuppressive therapy playing a pivotal role. The implementation of a National Registry would be the first step in an attempt to optimise immunosuppression in this particular group of patient's.

[Correlation between the onset of early proteinuria and the outcome of renal transplantation. Experience of a single centre]. / Correlazione tra insorgenza di proteinuria precoce e decorso clinico del rene trapiantato. Esperienza di un singolo centro.

BACKGROUND: Proteinuria is associated with an increased risk of renal failure. In chronic kidney transplant failure it is associated with poorer graft outcome. MATERIALS AND METHODS: In our Unit 405 renal transplants were performed between April 1992 and December 2001. We analysed 1) the main causes of post-transplant proteinuria and 2) the prognostic significance for graft outcome in patients with a minimum follow-up of 6 months. RESULTS: Early proteinuria was associated with a higher incidence of chronic allograft nephropathy (CAN) and de novo/recurrent nephropathies. Graft outcome was poorer in patients with early persistent proteinuria. CONCLUSIONS: Proteinuria after renal transplantation increases the risk of graft failure. We can, therefore, hypothesize that a graft biopsy is the best way to reveal the causes of proteinuria so that therapeutic interventions, which have been shown to reduce proteinuria, can be applied immediately.