Steroid-resistant Minimal Change Disease Research Articles

#3057 OUTCOMES IN SRNS (FSGS) PATIENTS IN THE UK RADAR IDIOPATHIC NEPHROTIC SYNDROME REGISTRY AND THEIR RELATIONSHIP WITH TIME-AVERAGED PROTEINURIA

Abstract Background and Aims Idiopathic Steroid Resistant Nephrotic Syndrome, SRNS (incorporating FSGS) is an important cause of proteinuric renal disease leading to kidney failure. Here we describe the outcomes of SRNS using the UK National Registry of Rare Kidney Diseases Idiopathic Nephrotic Syndrome (RaDaR-INS) Cohort, including retrospective and prospective data from 4274 patients with nephrotic syndrome (NS) not attributable to glomerulonephritis or systemic disorders, recruited from 107 adult and paediatric kidney units across the UK since 2010. In patients with FSGS, severity of proteinuria at onset and during follow up is associated with renal failure. In this study, we tested for associations between defined proteinuria endpoints with both eGFR slope and renal survival, in children and adults. Method Participants included those with renal biopsy diagnosis of FSGS or minimal change disease (MCD), or monogenic NS. Patients with no proteinuria measurement ≥1.0 g/g >6 months after disease onset were excluded as likely fully steroid-sensitive. Patients with kidney failure (KF) (CKD stage 5 or on renal replacement therapy) at or prior to first proteinuria measurement after baseline were excluded. Disease onset was defined as time of renal biopsy; primary renal diagnosis (PRD) date if no biopsy date recorded, and first proteinuria ≥1 g/g if neither biopsy/PRD date was available. Baseline was defined as first proteinuria ≥1 g/g >6 months after disease onset. Kaplan-Meier methods were used to analyze renal survival, defined as absence of KF or death with survival time calculated from baseline to last follow up. eGFR slope was measured from 6 months after baseline for the duration of follow up. Results Of 612 MCD and FSGS patients meeting eligibility, median time from disease onset to baseline was 1.2 years (IQR 0.6-4.4). Median baseline age was 38 years (IQR 21–56) with paediatric patients representing 21% of the study population. Median proteinuria at baseline was 3.4 g/g (IQR 1.9-6.2), while mean eGFR was 89 mL/min/1.73 m2 (SD 39). Mean rate of loss of eGFR over follow-up was 4.4mL/min/1.73 m2/year (SD 10.9). Complete proteinuria remission (CR) and FSGS partial remission (FPR) were defined as shown in Table 1 using values of time-averaged proteinuria (TA-PU) over months 6–24 from baseline. For patients achieving CR or FPR, the rate of loss of eGFR was slower (Table 1), with a higher probability of survival from KF/death (Table 1 & Figure 1), than patients failing to achieve CR or FPR. Conclusion This is a study of proteinuria and outcomes in a population of patients with FSGS or steroid-resistant MCD. We regard the latter group as likely also to have FSGS. In this population of patients with overt proteinuria, achieving partial or complete remission of proteinuria is associated with slower disease progression and reduced risk of KF/death.

Steroid-Resistant Minimal Change Disease Induced by Waldenstrom Macroglobulinemia

Steroid-Resistant Minimal Change Disease Induced by Waldenstrom Macroglobulinemia

The Beneficial Effect of Combination of Mycophenolate with Low-Dose Corticosteroids and Calcineurin-Inhibitor as Well as Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Blocker in Induction and Maintenance of Remission in Corticosteroid- and Rituximab-Resistant Minimal Change Nephrotic Syndrome in Adults

Management of steroid-resistant minimal change disease remains elusive with international guidelines suggesting high-dose corticosteroids and/or Calcineurin inhibitors for months similar to those with refractory idiopathic FSGS. Unfortunately, with such approach, the overall remission rates were 47% - 66%. Moreover, complete remission rates were 32% - 47% and partial remission ones were 19% - 29%. Those limited options of treatment and their poor outcomes led us to conduct the present study to assess the efficacy and safety of a new combined drug-therapy at induction and subsequent maintenance of such disease. The regimen consisted of an initial induction phase of 3-month Prednisone, Calcineurin-inhibitor, Mycophenolate and ACEI/ARB. The latter was followed by a maintenance phase of minimal dose Prednisone and nearly 1/2 the induction dose of Calcineurin inhibitors to decrease their long-term side effects. The results were satisfactory with 14 of the 22 patients, had complete remission. Moreover, 5 patients manifested partial remission and only 3 did not respond. Creatinine clearance was maintained in patients with complete remission yet, was mildly reduced in the partial and non-responsive ones. The safety and efficacy of such new combined drug-therapy provide new tool and future prospective in management of such relentless disease.

Spontaneous Bacterial Peritonitis in an Adult Patient with Minimal Change Disease

Patient: Male, 60-year-oldFinal Diagnosis: PeritonitisSymptoms: Abdominal pain • edema of lower extermitiesMedication: —Clinical Procedure: —Specialty: NephrologyObjective:Rare diseaseBackground:Pediatric patients with nephrotic syndrome have a high risk of developing spontaneous bacterial peritonitis (SBP). However, SBP in adults with nephrotic syndrome is very rare. We report a case of SBP induced by Escherichia coli in a 60-year-old male patient on immunosuppressive therapy for the treatment of minimal change disease (MCD).Case Report:The patient was hospitalized with abdominal pain and generalized edema that had lasted for 2 weeks. The patient first started treatment with high-dose oral prednisolone after being diagnosed with MCD 6 months ago. Complete remission of nephrotic syndrome was not achieved even after 5 months of treatment. Thus, the treatment was changed to combination therapy with cyclosporine and low-dose prednisolone. At the time of admission, leukocytosis, hypoalbuminemia, decreased serum immunoglobulin G (IgG), azotemia, and nephrotic-range proteinuria were observed. Ascitic fluid analysis showed a leukocyte count of 4960/μL (neutrophils 90%). On the suspicion of SBP associated with MCD, intravenous administration of empirical cefotaxime and supportive therapy were initiated; however, symptoms of peritonitis persisted. Extended-spectrum beta-lactamase-negative E. coli was found in ascites cultures. Laparoscopy-assisted peritoneal biopsy revealed no evidence of fungal infection; however, chronic inflammation without granuloma formation was noted. Afterward, cefotaxime was changed to piperacillin-tazobactam. After 4 weeks of antibacterial therapy, the peritonitis was cured and renal function was improved.Conclusions:Adult patients with steroid-resistant MCD accompanied by refractory ascites, severe hypoalbuminemia, and marked reduction in serum IgG are at a high risk of subsequent SBP and require careful monitoring.

Continuous B-cell depletion in frequently relapsing, steroid-dependent and steroid-resistant nephrotic syndrome.

BackgroundPatients with frequently relapsing (FR), steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome are a therapeutic challenge with limited treatment options. Here, we retrospectively analyze the efficacy and safety of rituximab-induced continuous B-cell depletion in these populations.MethodsPatients were included if they were at least 18 years of age and had FR, SD or SR minimal change disease (MCD) or primary focal segmental glomerulosclerosis (FSGS) and were treated with a strategy of continuous B-cell depletion. Partial remission (PR) was defined as a urinary protein:creatinine ratio (UPCR) of ≤3.5 g/g and a 50% reduction in the UPCR from baseline. Complete remission (CR) was defined as a UPCR ≤0.3 g/g.ResultsWe identified 20 patients with MCD (n = 13) or FSGS (n = 7) who fulfilled the inclusion criteria. All patients had either SD (n = 12), SR (n = 7) or FR (n = 1) disease. Patients received a median of nine rituximab doses [interquartile range (IQR) 7.5, 11] and were treated for a median time of 28 months (IQR 23, 41). Prednisone was weaned from a median of 60 mg daily (IQR 40, 60) at rituximab initiation to 4.5 mg daily (IQR 0, 5.5) by 12 months. All patients achieved PR. CR occurred in 11 of 13 patients with FR or SD disease, but only 1 of 7 patients with SR disease (logrank P = 0.01). Four relapses occurred, all in patients with SR disease. Three serious infections occurred over 70.3 patient-years.ConclusionContinuous B-cell depletion is a therapeutic option in the management of complicated nephrotic syndrome. Additional studies are needed to clarify the utility of this strategy.

Steroid-resistant minimal change disease with ballooned podocytes

Steroid-resistant minimal change disease with ballooned podocytes

A Case of Steroid Resistant Minimal Change Disease Associated with Portal Vein Thrombosis Treated by Combined Immunosuppressive Agents

Minimal change disease (MCD) is a common cause of nephrotic syndrome and relatively well responds with steroid treatment. However, nearly half of patients with MCD experience recurrence of nephrotic syndrome. Thromboembolic events including renal vein thrombosis may occur in patients with MCD, but portal vein thrombosis rarely occurs. We experienced a case of frequent relapse/steroid dependent MCD with nephrotic syndrome progressed to steroid resistance associated with portal vein thrombosis. This patient showed complete remission of MCD and resolution of portal vein thrombosis after treatment with corticosteroid, cyclosporine, mycophenolate mofetil, and anticoagulant.

Efficacy and safety of leflunomide in treatment of steroid-dependent and steroid-resistant adult onset minimal change disease

To observe the efficacy and safety of leflunomide combined with prednisone therapy (LEF therapy) in the treatment of patients with adult onset steroid-dependent and steroid-resistant minimal change disease (MCD). 16 MCD patients who had been treated with LEF therapy were retrospectively analyzed. 87.5% (14/16) of the patients were steroid-dependent and 12.5% (2/16) of the patients were steroid-resistant. The initial dose of LEF was 10 - 20 mg/day combined with prednisone 0.25 - 1.0 mg/kg/day, gradually tapering after 8 weeks. Clinical and laboratory data at baseline, 2nd, 4th, 8th, 12th, 24th, and 48th week were analyzed compared with initial course of prednisone monotherapy (PRED monotherapy) and cyclophosphamide combined with prednisone therapy (CTX therapy). All the 16 patients achieved different levels of remission in LEF therapy. 93.8% (15/16) of the patients, including the two steroid-resistant patients, achieved complete remission. During the treatment, 8 patients had adverse effects which could be well tolerated. Compared LEF therapy with PRED monotherapy (n = 16), the dose of prednisone to maintain remission was reduced (from median 22.5 mg/day to median 7.5 mg/day, p = 0.041); relapse rate during the follow-up decreased from 100% to 31.3% (p = 0.002); the median time before relapse increased from 20.3 weeks to 32.5 weeks. Compared LEF therapy with CTX therapy (n = 12), the dose of prednisone to maintain remission was reduced significantly (from median 22.5 mg/day to median 5.0 mg/day, p = 0.003); relapse rate during the follow-up decreased from 100% to 31.3% (p = 0.001); the median time before relapse increased from 11.7 weeks to 32.5 weeks. LEF therapy seems to be effective in steroid-resistant and steroiddependent MCD. This therapy may reduce the amount of prednisone to maintain remission and reduce the relapse rate compared with PRED monothrerapy and CTX therapy. LEF therapy was usually well tolerated.

Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure

Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-α (RARα)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARα agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phoshodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARα agonists to provide additional renal protection.

Ponticelli regimen and nephrotic syndrome

Sir, We read the article of Das et al.[1] with interest; it raised few questions that beg answers. Both in children and adults with steroid resistant minimal change disease (MCD) and focal segmental glomerulo sclerosis (FSGS), cyclosporine is the preferred choice.[2] Cytotoxic drug (cyclophosphamide) is indicated in frequent relapsing and/ or steroid dependent/toxicity group of MCD pediatric patients. The article was a mixture of frequent relapsers and steroid resistant nephrotic syndrome (SRNS). It is possible that the patients who improved with this protocol were only frequent relapsers, not affected with SRNS. Presuming that only cyclophosphamide (cytotoxic drug) is sufficient, addition of high dose of steroid adds to the steroid toxicity. The addition of prednisone to the cytotoxic drug may not improve the efficacy of the regimen, but it allows the patient for high fluid intake to protect against the cystitis. In such a case, the dose of steroid is tapered once remission is achieved.[3] The authors were not explicit about the use of the terms, ‘frequent relapsers’ and ‘steroid resistant’ in the context of membranoproliferative glomerulonephritis and IgA nephropathy. IgA nephropathy is treated when proteinuria >1 g/24 h with preserved renal function with steroid for six months and with progressive renal failure (serum creatinine <2.84 mg/dl), a cytotoxic agent is added. The treatment in the latter group is at least for two years.[4] It is surprising that the lone IgA nephropathy with FR (sic) and renal impairment achieved remission and improvement in renal function at the end of six months. Results in fact did not present clinical and laboratory features of each group of the disease. With expanding armamentarium to treat nephrotic syndromes, based on it etiology, proteinuria, renal impairment, renal biopsy features and individual merit, the authors surprisingly presented a unifying concept of a common treatment to all nephrotic syndromes, irrespective of its etiology. Is there a message, that the renal biopsy is, now, redundant; treat all with steroids, but if there is no response, use this protocol.[1] The definition used for ‘renal failure’ in the article was persistent doubling of plasma creatinine over baseline value but the highest serum creatinine, mentioned only in Table 4, was only 1.12 + 0.58 mg/dl. In Table 3, another term ‘renal insufficiency’ was used, but it was not defined in the article.

137: Steroid Resistant Minimal Change Disease Associated With Thymoma: A Case Report

STEROID RESISTANT MINIMAL CHANGE DISEASE ASSOCIATED WITH THYMOMA: A CASE REPORT Rakesh Lattupalli, Quresh Khairullah, Keith Bellovich, Joel Topf. Division of Nephrology, St John Hospital and Medical center, Detroit, Mi, USA Background: The association of glomerulonephritis and thymic tumor was first described by Posner et al in 1980 . The association is quite low; <1% in surgical series. A total of 21 cases have been reported in the French and English literature. Minimal change disease (MCD) is the most frequent (67%) thymoma associated glomerular lesion. Fortunately the majority (84%) of these patients are steroid sensitive. We report a case of steroid resistant thymoma associated MCD. Case Report: A 63-year-old male with past medical history of diabetes mellitus for six years was referred for new onset nephrotic syndrome. Kidney biopsy revealed MCD. The proteinuria did not respond to steroids. Further diagnostic tests revealed a mediastinal mass. Following removal this was diagnosed as spindle cell thymoma. Post thymectomy hypoalbuminemia persisted despite modest reduction in proteinuria. The patient continued to have edema resistant to diuretic therapy and eventually was started on dialysis. Discussion: The pathogenesis of glomerular lesions in thymoma related minimal change disease remains controversial. The beneficial effect of immunosuppressive therapy in most patients suggests a link between the immune system and MCD. Animal studies suggest that thymectomy does not modify the nephropathy. Further studies of this association between nephrotic syndrome and thymoma are needed to define the specific immune dysregulation associated with this disorder.

Fulminant ulcerative colitis associated with steroid-resistant minimal change disease and psoriasis: A case report

A 43-year-old Chinese patient with a history of psoriasis developed fulminant ulcerative colitis after immunosuppressive therapy for steroid-resistant minimal change disease was stopped. Minimal change disease in association with inflammatory bowel disease is a rare condition. We here report a case showing an association between ulcerative colitis, minimal change disease, and psoriasis. The possible pathological link between 3 diseases is discussed.

Combination of Immunosuppressive Agents in Treatment of Steroid-Resistant Minimal Change Disease and Primary Focal Segmental Glomerulosclerosis

Background. Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most prevalent histopathological lesions in idiopathic nephrotic syndrome (INS). The latter is associated with high morbidity and mortality due to symptomatic anasarca, bacterial infections, venous and arterial thromboembolism, and potential progression to end-stage renal disease in the case of FSGS. Traditionally, most patients are treated with corticosteroids, cyclophosphamide (CTX) or calcineurin-inhibitors (C-I). Unfortunately, many patients become steroid or C-I dependent, with the inherent risk of long-term side effects, or are resistant to both. The aim of this paper is to report on our experience with a new protocol of a combination of immunosuppressive agents added sequentially to improve the response of steroid and C-I refractory or resistant-INS and to minimize the long-term side-effects of single-agent treatment. Methods. Twenty-one patients with corticosteroid-resistant and C-I refractory INS (6 with MCD and 15 with FSGS) were treated prospectively over 6 and a half years. Our protocol consisted of an initial regimen of C-I followed by the addition of mycophenolate mofetil (MMF) and then by monthly intravenous CTX for 3 consecutive months. Dose reduction of C-I or/and MMF was attempted afterwards at 4-months intervals. Patients who remained refractory to the previously mentioned protocol were treated with an additional course of pulse Solu-Medrol given for 3 days followed by oral corticosteroids tapered over 6 months in addition to a second course of intravenous CTX given for 3 consecutive months. Results. With the initial regimen, two patients with MCD, remained in complete remission (CR) without any therapy after the course of CTX. Fifteen patients had variable response to C-I and MMF, but they achieved CR after CTX and their initial dosage of C-I and MMF were reduced to nearly one half. The remaining four patients had refractory form of FSGS even after the initial regimen, yet responded with CR to the additional course of steroid/CTX. However, no success with dose-reduction, in C-I and MMF, was achieved in the latter four patients. Conclusion. Our study represents the first clinical trial with prospective and adequate follow-up of combination therapy of immunosuppressive agents in INS. This method is effective and safe for treatment of patients who are refractory to the conventional single-agent therapy.

Recurrent minimal change disease post-allograft renal transplant

A young adult was diagnosed with steroid-resistant minimal change disease (MCD) without evidence of focal segmental glomerulosclerosis (FSGS) despite serial and detailed sectioning and screening of the renal biopsy. He received initial treatment with steroids and then cyclosporine plus low-dose steroids for 2 years. Renal function progressively deteriorated due to resistance to steroid and cyclosporine. Two months after initiation of hemodialysis, the patient received a living-related allogenic kidney transplant. However, recurrent nephrotic syndrome and renal insufficiency occurred after transplantation. In spite of aggressive treatment, renal function showed no significant improvement. The kidney graft was removed 2 weeks after transplantation. Serial sectioning and thorough sampling and screening revealed no evidence of FSGS, but light microscopy and electron microscopy showed the typical morphologic pattern of MCD, corresponding to the pretransplant diagnosis. We believe that this is the first reported case of recurrent MCD after renal transplant.

Successful treatment of steroid-resistant minimal change disease with mycophenolate mofetil

Mycophenolate mofetil has been reported to be effective in the treatment of steroid-responsive minimal change disease. We report a case of steroid- and cyclosporin-resistant minimal change disease with severe nephrotic syndrome that responded to mycophenolate mofetil with complete remission. The patient remains in complete remission 1 year after the discontinuation of mycophenolate mofetil. The presented case argues for the need of a prospective controlled study with the goal of evaluating the efficacy of mycophenolate mofetil in the therapy of steroid-resistant minimal change disease.

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis

Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis

Long-term results of cyclosporine-induced remission of relapsing nephrotic syndrome in children.

Twenty-nine children with nephrotic syndrome were treated with cyclosporine (CsA), 100 mg/m2/day for 6 months and prednisone, 2 mg/kg every other day for 1 month and then subsequently 1 mg/kg every other day for 5 months. A renal biopsy had shown minimal change disease (MCD) in 18 children, focal segmental glomerulosclerosis (FSGS) in 3 children, membranous glomerulonephritis (MGN) in 4 children, membranoproliferative glomerulonephritis (MPGN) in 2 children, and IgA nephropathy in 2 children. All MCD patients went into complete remission during therapy. Five out of 11 steroid-sensitive patients (45.5%) remained in complete remission, while the remaining 6 (54.5%) had 2 to 3 relapses, 19 to 47 months after CsA discontinuation. Two out of 7 steroid-resistant patients (28.6%) were still in complete remission and 5 (71.4%) had 1 to 6 relapses 25 to 49 months after CsA withdrawal. The mean number of relapses in the steroid-sensitive group before and after CsA treatment decreased more (8.5 vs 1.4) than in the steroid-resistant group (8.1 vs 2.4) (p < 0.05). At the most recent examination, 1 of 3 FSGS patients achieved complete remission and 2 had a partial response. Three of 4 MGN patients were in complete remission and 1 was in partial remission. One of 2 MPGN patients achieved complete remission and 1 showed partial remission. Two patients with IgA nephropathy were in partial remission. We compared MCD patients in sustained remission and relapse; the mean CD4/CD8 ratio decreased from 1.5 to 0.9 in the remission group, in comparison with no change in the relapsed group (p < 0.05). The posttreatment renal biopsy showed lesions of nephrotoxicity in 3 of 18 children with MCD whose renal function did not alter after CsA treatment. We concluded: 1) A 6-month treatment of CsA, in combination with a low-dose alternate-day steroid, proved to be effective in maintaining the remission of steroid-sensitive and steroid-resistant MCD patients. 2) The CD4/CD8 ratio can be used as a index to predict remission or relapse after CsA therapy.

1575 IDIOPATHIC NEPHROTIC SYNDROME: LONG-TERM PROGNOSIS

The clinical course of idiopathic nephrotic syndrome (NS) was studied in 65 children (mean age 3.3 yrs, range 1-14 yrs) who were either steroid responsive (61 pts) or had steroid-resistant minimal change disease (4 pts) at onset. All pts were followed for a minimum of 10 yrs (range 10-25 yrs) and follow-up was 15 yrs in 29 pts (45%).Of the 61 steroid responsive pts, 53 had a frequently relapsing-steroid dependent course. Of these pts, 20 were treated with cytoxan which induced a permanent remission in 13 (mean duration 8.7 yrs, range 6-12 yrs) and significantly reduced the rate of relapses in 4 others. Of the 33 pts not given cytoxan, 35% continue to experience relapses 10-18 yrs after onset while the others have been in remission for the past 2-16 yrs (mean 7.6 yrs).Of the 4 pts with steroid resistant minimal change disease, 3 were treated with cytoxan and all achieved a remission. Two of these pts have had no relapses 10 and 12 yrs after onset and 1 pt had a single relapse.At the completion of follow-up (mean 14.4 yrs), all pts have normal renal function (Scr < 1.5 mg/dl), 17% have BP ≥ 140/80 and 76% have a height which is < 50%tile (adjusted for sex and age) while 33% are < 25%tile for height. These findings suggest that in children with steroid responsive NS or steroid resistant minimal change disease there is: a) a favorable long-term outcome; b) the duration of relapsing disease is reduced by treatment with cytoxan and c) short stature is a significant consequence of therapy.