Idiopathic hypereosinophilic syndrome in hemodialysis patients: Case reports.

RATIONALE: Herein, we report 3 hemodialysis patients with idiopathic hypereosinophilic syndrome who were successfully treated using corticosteroid therapy. PATIENT CONCERNS: Case 1 was a 63-year-old man who was undergoing hemodialysis because of bilateral nephrectomy and developed hypereosinophilia with digestive symptoms, myocardial injury, and intradialytic hypotension. Case 2 was an 83-year-old man who was undergoing hemodialysis because of nephrosclerosis and developed hypereosinophilia with pruritus, myocardial injury, and intradialytic hypotension. Case 3 was a 59-year-old man who was undergoing hemodialysis because of diabetic nephropathy and developed hypereosinophilia with pruritus, myocardial injury, and intradialytic hypotension. DIAGNOSES: All 3 patients presented with hypereosinophilia (eosinophil count ≥1500 /µL for more than 1 month) and multiple-organ involvement (intradialytic hypotension, cardiac injury, digestive symptoms, and allergic dermatitis). A specific cause for the hypereosinophilia was not identified by systemic computed tomography, electrocardiography, echocardiography, bone marrow examination, or blood tests. Furthermore, Case 2 and 3 had not recently started taking any new drugs and drug-induced lymphocyte stimulation tests were negative in Case 1. Therefore, they were diagnosed with idiopathic hypereosinophilic syndrome. INTERVENTIONS: All 3 patients received corticosteroid therapy with prednisolone at a dose of 40 mg/d, 30 mg/d, and 60 mg/d in Case 1, 2, and 3, respectively. OUTCOMES: Their digestive symptoms, pruritus, intradialytic hypotension, and serum troponin I concentrations were immediately improved alongside reductions in their eosinophil counts. LESSONS: There have been few case reports of idiopathic hypereosinophilic syndrome in patients undergoing hemodialysis. We believe that recording of the clinical findings and treatments of such patients is mandatory to establish the optimal management of idiopathic hypereosinophilic syndrome.

Clinical Outcomes after Endovascular Therapy Among Hemodialysis Patients with Peripheral Artery Disease Stratified by the Primary Kidney Disease.

OBJECTIVES: The objective of this study was to investigate the clinical characteristics of hemodialysis patients with peripheral artery disease (PAD) and the outcomes after endovascular therapy (EVT) in such patients stratified by the primary kidney disease. METHODS: This retrospective observational study evaluated 142 consecutive hemodialysis patients with symptomatic PAD who underwent EVT (men: n = 103, age: 74 ± 8 years). Patients were divided into 3 groups in accordance with the reason for hemodialysis: hypertensive nephrosclerosis (HTN [n = 26]), diabetic nephropathy (DN [n = 85]), and chronic glomerulosclerosis (CGN [n = 31]). The primary outcome was major adverse event(s) (MAEs), including target lesion revascularization, major amputation, and all-cause death. Clinical characteristics and outcomes were compared among the 3 groups. RESULTS: Patients with HTN were older (81 ± 6 years vs. 72 ± 8 years vs. 74 ± 8 years; P < 0.001) and had a shorter hemodialysis vintage (2.4 years vs. 6.8 years vs. 11.2 years; P < 0.001) than those with DN and CGN. Critical limb ischemia (CLI) affected 15 (58%) patients in the HTN group, 52 (61%) in the DN group, and 10 (32%) in the CGN group. Target lesion length was longer in patients with HTN than in those in the other groups (155 ± 101 mm vs. 108 ± 77 mm [DN] vs. 98 ± 76 mm [CGN]; P = 0.020). During a median follow-up period of 372 days (interquartile range, 198-730 days), Kaplan-Meier curve analysis revealed that HTN was associated with an increased risk for MAEs (χ2 11.6; P = 0.003). Furthermore, multivariate Cox regression analysis revealed that CLI, HTN, and B-type natriuretic peptide levels were independent predictors of MAE (hazard ratio 3.91, 2.88, and 1.00; P < 0.001, P < 0.001, and P = 0.001, respectively). CONCLUSIONS: Among hemodialysis patients with PAD, HTN was associated with an increased risk for MAEs after EVT.

Peritonitis due to Moraxella osloensis: A case report and literature review.

A-26-year-old man was admitted to our hospital with diffuse abdominal pain, nausea, and vomiting. He had a history of malignant nephrosclerosis, for which he had been receiving peritoneal dialysis (PD) for the past 14 months. His PD effluent was cloudy and turbid (white blood cell count, 10,528/µL; neutrophils 95.2%). A Gram-negative coccobacillus was isolated from peritoneal fluid culture. However, the organism could not be identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) (Vitek MS, bioMérieux), but was identified as Moraxella osloensis by the 16S rRNA gene sequencing. He was successfully treated with intraperitoneal cefazolin therapy for 3 weeks without removing the intra-abdominal catheter. A literature review revealed three previous case reports all of which were diagnosed by MALDI Biotyper (Bruker Daltonics), suggesting that the identification of M. osloensis may vary depending on the type of MALDI-TOF MS system. In conclusion, we experienced a case of M. osloensis infection in a PD patient, which was successfully treated by antibiotic treatment, without removing the PD catheter.

Volume Ratio of Glomerular Tufts to Bowman Capsules and Renal Outcomes in Nephrosclerosis.

BACKGROUND: The concomitant appearance of glomerular collapse and enlargement is characteristic of the histological findings in nephrosclerosis. However, no previous study quantitatively examined the clinicopathological significance of this feature in patients with biopsy-proven nephrosclerosis. METHODS: Renal biopsy specimens and follow-up data from nephrosclerosis patients with estimated glomerular filtration rates >30 ml/min/1.73 m2 at diagnosis were retrospectively reviewed. Mean volumes for glomerular tufts (GV) and Bowman capsules (BV) were separately calculated, based on the measurement of all areas of glomerular tufts and Bowman capsules in a cross-section of biopsy specimens. The G/B ratio was defined as the ratio of GV to BV. The doubling of serum creatinine levels (DSC) and the initiation of renal replacement therapies (end-stage renal disease (ESRD)) were examined as renal outcome indices. RESULTS: A total of 67 patients with biopsy-proven nephrosclerosis were included. Clinicopathological findings at biopsy, other than GV, were comparable among all patients, irrespective of G/B ratio. Overall, 25 patients (37%) developed DSC and 9 (13%) developed ESRD during the median observation periods of 7.8 and 8.5 years, respectively. Renal survival curve analyses indicated a significantly worse prognosis for patients with a low G/B ratio, as compared with those with a high G/B ratio. Cox hazard analyses for DSC identified low G/B ratio as a significant predictor, but not low GV or BV. CONCLUSIONS: These results suggest that the quantitative evaluation of G/B ratio may detect subtle abnormalities in the glomerulus, indicating the subsequent renal outcomes of nephrosclerosis patients.

First case report of using Ofatumumab in kidney transplantation AB0 incompatible. / PRIMO CASE REPORT DI UTILIZZO DELL' OFATUMUMAB NEL TRAPIANTO RENALE AB0 INCOMPATIBILE.

Modern methods for desensitization protocol rely heavily on combined apheresis therapy and Rituximab, a chimeric (murine and human) anti-CD20 antibody used in AB0 incompatible kidney transplants. Severe infusion related reactions due to the administration of Rituximab are reported in 10% of patients. These adverse reactions may hinder the completion of the desensitization protocol. Therefore, it's useful to test alternative B cell depleting therapies. Our clinical case focuses on a 41-year-old male who developed an adverse infusion reaction following the administration of Rituximab and was given Ofatumumab as an alternative treatment. Ofatumumab is a fully humanized monoclonal anti-CD20 antibody. As a fully humanized antibody, Ofatumumab may avoid immunogenic reactions. The patient tolerated the administration of the drug showing no signs of adverse side effects and with good clinical efficacy. Our case report suggest that Ofatumumab is a valid alternative B cell depleting agent.

Comparison of Clinical Trajectories before Initiation of Renal Replacement Therapy between Diabetic Nephropathy and Nephrosclerosis on the KDIGO Guidelines Heat Map.

This study investigated differences between the clinical trajectories of diabetic nephropathy and nephrosclerosis using the Kidney Disease: Improving Global Outcomes (KDIGO) heat map and the clinical characteristics between the two diseases at RRT initiation. This single-center, retrospective study enrolled 100 patients whose estimated glomerular filtration rate (eGFR) was ≥45 mL/min/1.73 m(2) at their first visit and who were initiated on RRT. Fifty consecutive patients were assigned to each of the diabetic nephropathy and nephrosclerosis groups. All data for simultaneously measured eGFR and urinary albumin to creatinine ratio (UACR) were collected from first visit to RRT initiation and were plotted on the KDIGO heat map. Diabetic nephropathy was characterized by higher blood pressure and UACR and lower age, eGFR, and serum albumin levels compared with nephrosclerosis at RRT initiation. The vast majority of patients with diabetic nephropathy and eGFR < 60 mL/min/1.73 m(2) had concomitant macroalbuminuria, whereas for patients with nephrosclerosis, even when eGFR was <45 mL/min/1.73 m(2), many still had normoalbuminuria or microalbuminuria. The rate of decline of eGFR was significantly faster in the diabetic nephropathy group than that in the nephrosclerosis group. The clinical trajectories of diabetic nephropathy and nephrosclerosis differed markedly on the KDIGO heat map.

The Different Association between Serum Ferritin and Mortality in Hemodialysis and Peritoneal Dialysis Patients Using Japanese Nationwide Dialysis Registry.

BACKGROUND/AIMS: Monitoring of serum ferritin levels is widely recommended in the management of anemia among patients on dialysis. However, associations between serum ferritin and mortality are unclear and there have been no investigations among patients undergoing peritoneal dialysis (PD). METHODS: Baseline data of 191,902 patients on dialysis (age, 65 ± 13 years; male, 61.1%; median dialysis duration, 62 months) were extracted from a nationwide dialysis registry in Japan at the end of 2007. Outcomes, such as one-year mortality, were then evaluated using the registry at the end of 2008. RESULTS: Within one year, a total of 15,284 (8.0%) patients had died, including 6,210 (3.2%) cardiovascular and 2,707 (1.4%) infection-related causes. Higher baseline serum ferritin levels were associated with higher mortality rates among patients undergoing hemodialysis (HD). In contrast, there were no clear associations between serum ferritin levels and mortality among PD patients. Multivariate Cox regression analysis of HD patients showed that those in the highest serum ferritin decile group had higher rates of all-cause and cardiovascular mortality than those in the lowest decile group (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.31-1.81 and HR, 1.44; 95% CI, 1.13-1.84, respectively), whereas associations with infection-related mortality became non-significant (HR, 1.14; 95% CI, 0.79-1.65). CONCLUSIONS: Using Japanese nationwide dialysis registry, higher serum ferritin values were associated with mortality not in PD patients but in HD patients.

The antifibrotic effect of a serine protease inhibitor in the kidney.

Interstitial fibrosis is a final common pathway for the progression of chronic kidney diseases. Activated fibroblasts have an extremely important role in the progression of renal fibrosis, and transforming growth factor (TGF)-ß1 is a major activator of fibroblasts. Since previous reports have indicated that serine protease inhibitors have a potential to inhibit TGF-ß1 signaling in vitro, we hypothesized that a synthetic serine protease inhibitor, camostat mesilate (CM), could slow the progression of renal fibrosis. TGF-ß1 markedly increased the phosphorylation of TGF-ß type I receptor, ERK 1/2, and Smad2/3 and the levels of profibrotic markers, such as α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1, in renal fibroblasts (NRK-49F cells), and they were all significantly reduced by CM. In protocol 1, 8-wk-old male Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO) and were concurrently treated with a slow-release pellet of CM or vehicle for 14 days. Protocol 2 was similar to protocol 1 except that CM was administered 7 days after UUO. CM substantially improved renal fibrosis as determined by sirius red staining, collagen expression, and hydroxyproline levels. The phosphorylation of ERK1/2 and Smad2/3 and the levels of α-SMA, CTGF, promatrix metalloproteinase-2, and matrix metalloproteinase-2 were substantially increased by UUO, and they were all significantly attenuated by CM. These antifibrotic effects of CM were also observed in protocol 2. Our present results suggest the possibility that CM might represent a new class of therapeutic drugs for the treatment of renal fibrosis through the suppression of TGF-ß1 signaling.

[Hypertensive emergency with clinical signs of a thrombotic microangiopathy]. / Hypertensiver Notfall mit den klinischen Symptomen einer thrombotischen Mikroangiopathie.

HISTORY AND ADMISSION FINDINGS: A 38-year-old woman presented with strong headache, abdominal and chest pain. Blood pressure was 240/115 mmHg. In the emergency room lab troponin T was elevated. Further tests showed signs of hemolysis and thrombopenia. In addition kidney failure was present. INVESTIGATIONS: The ECG showed tachycardia, but no other changes. Echocardiography revealed hypertrophy of the left ventricle. In the eye exam hypertensive retinopathy was demonstrated. Kidney biopsy showed signs compatible with malignant hypertension. TREATMENT AND COURSE: Due to chest pain and elevation of troponin T acute coronary syndrome was diagnosed. In combination with thrombopenia and hemolysis a thrombotic microangiopathy was suspected. Because of the hypertensive emergency malignant hypertension became a possible differential diagnosis. Unfortunately antiplatelet treatment precluded kidney biopsy right at the beginning. Thus, plasmapheresis was initiated together with antihypertensive treatment. Kidney biopsy was done after plasma exchange and confirmed the diagnosis of malignant hypertension. CONCLUSION: Diagnosis of malignant hypertension can be difficult because symptoms of thrombotic microangiopathy are frequently present. In many cases only the combination of history, exams of endorgan damage and clinical course is needed to confirm the diagnosis. Prompt and sustained lowering of the blood pressure is pivotal. Even after successful treatment patients keep an elevated cardiovascular risk and need a close follow up.

Need for education on the differential diagnosis between chronic glomerulonephritis and nephrosclerosis, and treatment of both conditions to reduce the number of patients requiring hemodialysis in Wakayama.

OBJECTIVE: We investigated the present state of, and trends in, hemodialysis therapy in Wakayama, with the aim of identifying present and future problems. METHODS: We compared the number of patients on maintenance hemodialysis, patients newly commencing hemodialysis each year, and proportion of diseases prompting the initiation of hemodialysis, between Wakayama and all Japan from 2002 to 2009, using the CD-ROM, "An overview of dialysis treatment in Japan," published by the Japanese Society for Dialysis Therapy. RESULTS: The number of patients on maintenance hemodialysis per head of population was higher in Wakayama than in all Japan throughout the study period. The number of patients newly commencing hemodialysis per head of population was higher in Wakayama than in all Japan from 2002 to 2004, but no significant difference was seen after 2005. The proportion of patients with chronic glomerulonephritis as the causative disease for hemodialysis initiation was higher in Wakayama than in all Japan. However, nephrosclerosis was less common as the causative condition in Wakayama than in all Japan. The proportions of the different causative diseases were similar in all patients on maintenance hemodialysis in Wakayama as in the newly initiated patients. Accordingly, some patients diagnosed with chronic glomerulonephritis might actually have nephrosclerosis, or treatment may be inadequate. CONCLUSION: In order to reduce the number of patients requiring maintenance hemodailysis, it is important to accurately differentiate between chronic glomerulonephritis and nephrosclerosis, and also to treat patients with either disease appropriately.

[Hypertensive nephrosclerosis]. / Néphroangiosclérose.

Hypertensive nephrosclerosis is the leading cause of end stage renal disease (ESRD) in France, however, in prospective clinical trials of hypertension, ESRD accounts only for a small fraction of all events (incidence rate 0.2 to 0.4% by year). Hypertensive nephrosclerosis is characterized histologically by a series of vascular injury, none of which is truly specific and that can be observed also in obesity or normal aging. Hypertensive nephrosclerosis is mildly symptomatic, but the prognosis is never benign, due to cardiovascular and renal burden. This unspecific presentation may explain why the diagnosis of hypertensive nephrosclerosis is easily carried by excess, the main differential diagnoses are atherosclerotic ischemic renal disease, poorly symptomatic primitive nephropathies or the sequelae of unnoticed malignant hypertensive nephrosclerosis. The very high prevalence of hypertensive nephrosclerosis in populations from African ancestry has suggested a genetic predisposition. MYH9/APOL1 gene variants have recently been identified and are strongly associated with hypertensive nephrosclerosis, however the pathophysiological link between these variants and renal disease is still unclear. The treatment is mainly based on blocking the renin angiotensin system, especially when proteinuria is present. The target blood pressure is less firmly established, the latest data from the AASK study, however, do suggest a benefit on progression of lower values < 135/80 or even < 130/80 mmHg, especially in patients with proteinuria.

Contrasting clinical outcomes between different modes of peritoneal dialysis regimens: two center experiences in China.

In the present study, we compared the clinical outcomes between two different modes of peritoneal dialysis (PD) and explored the possible role of volume overload in continuous ambulatory peritoneal dialysis (CAPD) patients. A longitudinal and a cross-sectional study were included. Patients received either an 'adaptative ultrafiltration (UF)' PD regimen, which focused on gradually increasing peritoneal ultrafiltration (PDi group), or traditional PD treatment (PDt group). Patients' demographic characteristics, nutritional status, fluid removal as well as fluid status were recorded. In the cross-sectional study, all clinically stable patients who were treated with CAPD for at least three months were enrolled and grouped according to their time on dialysis: short term, medium term, and long term. Both studies showed that PDi and PDt patients had distinct fluid removal patterns. PDt patients had decreased total fluid removal with worsening fluid status and deteriorating nutritional status, whereas PDi patients remained rather stable in relation to fluid removal, fluid status, and improving nutritional status. Cox regression analysis confirmed that the PDi group had better patient survival than the PDt group. Our data suggest that traditional and 'adaptative UF' PD therapy may have distinct fluid removal patterns over time on dialysis, and this unique pattern might partly explain the still unacceptable high mortality of long-term CAPD patients.

Association of serum adiponectin levels with all-cause mortality in hemodialysis patients.

OBJECTIVE: Adiponectin (ADPN) has been shown to protect against cardiovascular disease for the general population with problematic metabolic syndrome. However, it remains unclear whether ADPN is associated with mortality in patients on maintenance hemodialysis (HD). METHODS, PATIENTS OR MATERIALS: We selected 85 HD patients [51 men/34 women; mean age, 64+/-2 years; underlying kidney diseases, diabetic nephropathy in 36 patients (42.3%), chronic glomerulonephritis in 29 (34.1%), hypertensive nephrosclerosis in 10 (11.8%), and others in 10 (11.8%)] who survived for more than 3 months after the start of HD. We first measured serum ADPN levels and prospectively followed patients for the next 3 years. RESULTS: We were able to follow 74 of 85 patients; 59 survived, and 15 died. Serum log-transformed ADPN levels were negatively correlated with BMI (r=-0.43, p<0.01). Despite a similar BMI (20.7+/-0.8 vs. 20.3+/-0.4 kg/m(2)), the expired patients had significantly higher ADPN compared with the surviving patients (20.5 microg/ml [14.0-23.5] vs. 14.2 microg/ml [9.7-21.3], p<0.05). Cox-hazards multivariate regression analysis adjusted for conventional case-mix features (age, sex, and underlying kidney disease) revealed that serum ADPN became a significant determinant of all-cause mortality. There was a 10.3% risk increment for each 1-microg/ml increase in ADPN during the follow-up. Kaplan-Meier analysis revealed that patients with higher ADPN levels (> or =15 microg/ml) had a significantly lower survival rate compared with those with lower ADPN levels (<15 microg/ml) (76 vs. 92%, p<0.05). CONCLUSION: These results indicated that high rather than low ADPN independently predict total mortality in HD patients.

Functional polymorphism of the myeloperoxidase gene in hypertensive nephrosclerosis dialysis patients.

Myeloperoxidase (MPO) may play an important role not only in host defense reactions but also in local inflammations, especially in atherosclerotic diseases such as hypertensive nephrosclerosis (HN). Paradoxically, MPO-deficient mice have been reported to show increased atherosclerosis compared with wild mice, although higher MPO levels are thought to exacerbate atherosclerotic disease. To clarify the genetic role of MPO in HN, we examined the function and distribution of the -463G/A polymorphism located in the promoter region of the MPO gene with ex vivo flow cytometry analysis and a study in end-stage renal disease patients, respectively. This polymorphism has been reported to have a functional significance in vitro, with the A allele being associated with lower MPO expression. In the present study, we also found significantly higher reactive oxygen species (ROS) production with peripheral neutrophils isolated from subjects with the GG genotype compared with those from subjects with other genotypes by flow cytometry assay with 2-[6-(4'-amino) phenoxy-3H-xanthen-3-on-9-yl] benzoic acid (APF), which shows higher sensitivity with hypochlorite (OCl(-)). Genotyping the -463G/A polymorphism in HN, chronic glomerulonephritis (CGN) and diabetic nephropathy (DM) patients who were under hemodialysis treatment demonstrated that the GG genotype was more frequent in the HN group than in the CGN and DM groups. However, the distribution of the GG genotype in the HN group was similar to that in healthy individuals. Although the -463G/A polymorphism is associated with ROS production, careful interpretation may be required to conclude that the -463G/A polymorphism can serve as a useful marker of atherosclerosis and cardiovascular events in dialysis patients.

Recent perspectives in the mechanisms and therapy of renal sclerosis.

Chronic renal failure results from progressive sclerosis of injured kidney structures and overload of remnant functioning nephrons in an attempt to compensate for the lost excretory and fluid/solute regulatory capabilities. Key to delaying--or even reversing--the decay of renal function would be a therapy capable of blocking re-nal sclerosis. Therefore, a number of recent studies deal with this issue with a wealth of novel approaches. Considerable success has been achieved in experimental models by applying gene therapy, cell therapy, novel pharmacologic inhibitors of growth factors and matrigenic molecules. While the final step forward to human therapy is not an immediate option, it is likely that the next few years will witness initial trials of novel pharmacologic agents. Along with the already available new drugs suitable to prevent or delay renal transplant rejection or immunologic renal injury, the therapeutic scenario of contemporary nephrology is rapidly evolving. Some major novel findings in the area will be summarized, along with potential implications for human therapy.

Porphyria syndrome associated with diabetic nephrosclerosis and erythropoietin.

The porphyrias are inherited or acquired metabolic disorders caused by a partial deficiency in one of the enzymes of the heme biosynthetic pathway. Eight enzymes are utilized in the synthesis of heme. An enzyme defect in one of the last seven enzymes will result in one of the seven different forms of porphyria, some of which have similar signs and symptoms. This article describes six diabetic, azotemic patients with no prior history of porphyria, who developed a syndrome similar to acute intermittent porphyria after initiation of treatment with erythropoietin. One of the patients developed the syndrome predialysis, whereas the remaining patients were on maintenance hemodialysis. The symptoms varied but all resolved when erythropoietin was discontinued and reappeared in four cases when erythropoietin was restarted. In all of the patients, the enzyme aminolevulinic acid-dehydratase (ALA-D) was low and the uroporphyrinogen synthase was normal. This enzyme abnormality suggests an acquired form of delta-aminolevulinic acid dehydratase porphyria (ADP). Lead toxicity, succinylacetone, and zinc deficiency are known to depress ALA-D, but these conditions were not present. The development of the acute porphyria syndrome while the patients were receiving pharmacological doses of erythropoietin, which resolved when the drug was stopped, suggests that by stimulating heme synthesis, erythropoietin may unmask an enzyme deficiency resulting in the clinical expression of ADP. The patients responded favorably to a regimen that included discontinuation of erythropoietin, tight blood sugar control, maintaining the hematocrit above 30%, and a KT/V, a measure of dialysis adequacy, of 1.5 in the hemodialysis group. Plasmapheresis accelerated the recovery when used in two patients.

Rapid resolution of EPO-induced pure red cell aplasia after a course of immunoadsorption therapy using protein A columns.

Pure red cell aplasia (PRCA) is a rare, but important, complication of erythropoietin (EPO) replacement therapy in patients with renal disease. There is no consensus about the best way to treat this condition; however, recent reports indicated that immunosuppressive therapy is beneficial. We report a patient with EPO-induced PRCA treated with a regimen initially designed for antifactor VIII antibodies in patients with hemophilia. This regimen consists of immunoadsorption therapy using protein A columns, followed by oral prednisolone and single bolus infusions of intravenous immunoglobulin G and cyclophosphamide. Shortly after the course, a swift and rapid increase in reticulocyte count was evident; the patient became transfusion independent and has remained so during 2 years of follow-up. By means of this report, we wish to encourage others to consider this option when first-line treatments fail.