Remission Of Nephrotic Syndrome Research Articles

Modern view on treatment of membranous nephropathy

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Since the moment of animal model creation and the recognition of podocytes damage as a key mechanism of MN development, the identification of antigens, first of all the phospholipase A2 receptor (PLA2R), and the development of methods of PLA2R autoantibodies detection and its monitoring opened a new era in the idiopathic MN (iMN) diagnosis, treatment and prognosis evaluation. MN continues to be actively studied in the new millennium, since a number of aspects of its pathogenesis still need to be clarified, and there is still no clear opinion on the iMN treatment optimal approach. Comprehensive clinical and serological assessment of patients with iMN can be the key to individual choice of treatment protocols. In patients with aPLA2R-positive iMN, the predictor of disease remission is the aPLA2R titer decrease or aPLA2R disappearance in the blood serum, and disease relapse is associated with the aPLA2R appearance ore increase of aPLA2R titer in the circulation. Studies which were conducted by today (GEMRITUX, MENTOR, STARMEN, NICE, etc.) confirmed the acceptable safety profile and effectiveness of iMN therapy by anti-CD20 monoclonal antibodies (rituximab): more than half of of iMN patients had remission of nephrotic syndrome or proteinuria decrease, remissions in anti-CD20 monoclonal antibodies treated patients were longer compared to traditional therapy. The obtained data allows us to consider rituximab and anti-CD20 antibody therapy of a new generation not only as an alternative to the more toxic treatment with cyclophosphane and calcineurin inhibitors, but as an independent promising direction of therapy for patients with IMN, which completely changes the paradigm of treatment of this glomerulopathy.

Comparison of first choice cytostatic therapy with calcineurin inhibitors and nucleotides synthesis inhibitors in children with steroid-sensitive, steroid-dependent nephrotic syndrome with steroid toxicity

AIM. Evaluation in comparative study the efficiency of first choice cytostatic therapy with calcineurin inhibitor cyclosporine A and nucleotide synthesis inhibitormycophenolatemofetil (MMF)/mycophenolate sodium in children with relapsing and frequently relapsing steroid-dependent and steroid-sensitive nephrotic syndrome (NS) with steroid toxicity.PATIENTS AND METHODS. Follow-up study with analysis of onset, clinical course and treatment includes 48 children ((29 boys (60 %) и 19 girls (40 %)) with relapsing and frequently relapsing NS, developedsteroid dependence and/or steroid toxicity.The efficiency of first choice cytostatic therapy with calcineurin inhibitor cyclosporine Ain 17 patients and nucleotide synthesis inhibitormycophenolatemofetil (MMF)/mycophenolate sodium in 31 patients is estimated in comparative study by analysis of 6 month remission rate and one year remission rate after treatment.RESULTS. Statistically significant differences in 6 month and one year remission rate after first choice cytostatic therapy with MMF/ mycophenolate sodium and cyclosporine in children are established. Remission of NS during 6 months after MMF/ mycophenolate sodium treatment was in 67,7 % (in 21 from 31 patients) unlike of that after cyclosporine – in 29,4 % (in 5 from 17 patients) (р<0,05). Remission of NS during one year after MMF/ mycophenolate sodium treatment was in 58,1 % (in 18 from 31 patients) unlike of that after cyclosporine – 23,5 % (in 4 from 17 patients) (р<0,05). Cyclosporine toxicity was diagnosed in 5 from 17patients: increased creatinine (1),arterial hypertension (3), gingival hyperplasia (3) in treatment more than 12 months with reverse development after cancel. Side-effects after nucleotide synthesis inhibitor therapy was dignosed only in 1 from 31 patients (3,2 %) – lymphopenic crisis.CONCLUSION. Remission of relapsing and frequently relapsing steroid-dependent and steroid-sensitive with steroid toxicity NS during 6 months after first choice cytostatic therapy with MMF/ mycophenolate sodium and cyclosporine in children was in 67,7 % and 29,4 % respectively, during one year in 58,1 % and 23,5 % respectively. As the result of comparative study remission during 6 months and one year was statistically significant more often in children after first choice cytostatic therapy with MMF/ mycophenolate sodium.

Eosinophilic peritonitis and nephrotic syndrome in Kimura\u2019s disease: a case report and literature review

BackgroundEosinophilic peritonitis is a relatively rare entity. Kimura’s disease is a rare chronic inflammatory disorder of unknown etiology, characterized by subcutaneous nodules mainly in the head and neck region, regional lymphadenopathy and occasional involvement of kidney. There is currently no report of eosinophilic peritonitis in Kimura’s disease.Case presentationA 44-year-old Chinese man presented with abdominal distention, nausea, vomiting and edema in lower limbs for 1 month. Laboratory data showed elevated eosinophils in peripheral blood and ascites, nephrotic syndrome with progressively renal dysfunction, and elevated IgE. Ultrasonography of lymph nodes showed multiple lymphadenopathy in bilateral inguinal regions. Surgical excision was performed for one of the enlarged lymph nodes and histopathology revealed diagnosis of Kimura’s disease. Renal biopsy indicated focal segmental glomerulosclerosis (FSGS) and acute tubulointerstitial nephritis with infiltration of eosinophils in renal interstitium. The patient was prescribed with oral prednisolone therapy (30 mg/day), and underwent continuous ambulatory peritoneal dialysis (CAPD). The peripheral and peritoneal eosinophil count decreased rapidly and normalized within 2 days. Forty-five days after prednisolone therapy, partial remission of nephrotic syndrome and decrease of serum creatinine were achieved while peritoneal dialysis dosage had decreased. Inguinal lymph nodes gradually shrunk in size. The overall conditions remain stable afterwards.ConclusionsThis rare case highlighted the clinical conundrum of a patient presenting with eosinophilic peritonitis, lymphadenopathy, nephrotic syndrome and renal failure associated with Kimura’s disease. The remarkable eosinophilia, pathology of lymph node and kidney, as well as significant response to steroids should guide towards the diagnosis.

Relapse of Nephrotic Syndrome after Adrenocorticotropic Hormone-Induced Remission: Implications of Adrenocorticotropic Hormone Antibodies

Background: Prolonged use of corticosteroids continues to be the mainstay in the management of most proteinuric glomerulopathies, but is limited by extensive side effects. Alternative medications such as adrenocorticotropic hormone (ACTH) have been recently used to treat refractory glomerulopathies and have shown superior outcomes when compared with steroids. However, the clinical responsiveness to ACTH therapy varies considerably with a number of patients exhibiting de novo or acquired resistance. The underlying mechanism remains unknown. Methods: A patient with steroid-dependent focal segmental glomerulosclerosis (FSGS) developed severe steroid side effects impacting quality of life and was converted to repository porcine ACTH therapy. Immediate response in the form of remission of nephrotic syndrome was noted followed by relapse in 10 weeks. Suspecting the role of some ACTH-antagonizing factors, the patient’s serum was examined. Results: Immunoblot-based antibody assay revealed high titers of de novo IgG antibodies in the patient’s serum that were reactive to the porcine corticotropin with negligible cross-reactivity to human corticotropin. In vitro, in cultured B16 melanoma cells that express abundant melanocortin receptors, addition of the patient’s serum substantially abrogated the porcine corticotropin triggered signaling activity of the melanocortinergic pathway, marked by phosphorylation of glycogen synthase kinase 3β, thus suggesting a mitigating effect on the biological functionality of porcine corticotropin. Conclusion: ACTH is a useful alternative therapeutic modality for refractory proteinuric glomerulopathies like FSGS. However, as quintessential therapeutic biologics, natural ACTH, regardless of purity and origin, is inevitably antigenic and may cause the formation of neutralizing antibodies in some sensitive patients, followed by resistance to ACTH therapy. It is imperative to develop ACTH analogues with less immunogenicity for improving its responsiveness in patients with glomerular diseases.

Clinicopathological Spectrum of Renal Amyloidosis in Young.

Amyloidosis is a complex multi-system disorder characterized by deposition of an aberrant protein in tissues with kidney being the main target organ. The age of presentation of amyloid A (AA) amyloidosis is highest among adults aged 60-80 years followed by 45-55 years. However, presentation in younger age group is rare. We aimed to study the clinicopathological spectrum of patients with biopsy-proven renal AA amyloidosis aged <35 years in the last five years. This retrospective study was done on patients admitted from January 2015 to December 2019. Nine cases of AA amyloidosis diagnosed on kidney biopsy in ≤35 years of age were included in the study. Clinical, laboratory, and demographic data of all patients were obtained. Histopathological and direct immunofluorescence findings were further evaluated. The mean age (±standard deviation) was 22.5 ± 6.7 years with a range of 14-32 years. The most common underlying disorder of AA renal amyloidosis was Tuberculosis (TB) (88.88%, 8/9) with cyclosporine induced in one of the cases (11.11%). In all nine cases, glomeruli were mostly enlarged with moderate to marked mesangial expansion with thickened arteries and arterioles due to deposition of pink hyaline acellular material. Renal amyloidosis is rare in young age and is mostly secondary in nature. The association of TB with renal amyloidosis is common in adults (3.6%-50%), but only infrequently reported in children. It is important, especially in developing countries to be aware, as successful treatment of TB can result in remission of nephrotic syndrome due to secondary renal amyloidosis.

Atypical Presentation of Cytomegalovirus-Related Infantile Nephrotic Syndrome

Nephrotic syndrome is the most common glomerular disease in children. Most cases are idiopathic and the first episode is rarely related to cytomegalovirus infection, particularly after 3 months of age. We present a 7-month-old infant who developed atypical presentation of nephrotic syndrome secondary to cytomegalovirus infection. The patient was referred to undergo orchipexy due to right-sided undescended testis. Following the surgery, he developed fever, gastroenteritis and renal failure. A few days later, generalized edema and proteinuria were detected. Due to positive test results for cytomegalovirus, ganciclovir was administered. Remission of nephrotic syndrome was obtained within the first two weeks of the treatment. No relapse of nephrotic syndrome was detected during 12 months of follow up. We may conclude that in unexplained infantile nephrotic syndrome, CMV should be considered as one of the possible etiologies. Keywords: Nephrotic Syndrome; Cytomegalovirus; Infant; Ganciclovir; Edema; Proteinuria; Gastroenteritis.

Rituximab in Patients With Phospholipase A2 Receptor–Associated Membranous Nephropathy and Severe CKD

IntroductionPatients with phospholipase A2 receptor (PLA2R)–associated membranous nephropathy and stage 4 or 5 chronic kidney disease are at high risk of end-stage kidney disease. In recent years, rituximab (RTX) emerged as a safe and efficient treatment for patients with PLA2R-associated membranous nephropathy. Whether its use is also appropriate in patients with an estimated glomerular filtration rate <30 ml/min per 1.73 m2 has not been investigated.MethodsWe retrospectively reviewed characteristics and outcome of 13 patients with PLA2R-associated membranous nephropathy and stage 4 or 5 chronic kidney disease who received a total of 14 consecutive RTX treatments from January 2012 to March 2018. The treatment regimen consisted of either 2 weekly infusions of 375 mg/m2 or 2 RTX infusions of 1 g/d two weeks apart. When needed, the regimen was repeated to achieve immunological remission.ResultsThe mean estimated glomerular filtration rate, serum albumin level, and urinary protein level at the first RTX infusion were 18 ± 7 ml/min per 1.73 m2, 25.2 ± 5.4 g/l, and 13.2 ± 7.5 g/d, respectively, with all patients being tested positive for serum PLA2R antibodies. Ten treatment courses led to an increase in estimated glomerular filtration rate and remission of nephrotic syndrome after a median follow-up of 40.8 months (interquartile range, 14.8–46.8). Conversely, 4 RTX treatments were unsuccessful, with patients requiring chronic hemodialysis within 1 year. The urinary albumin-to-protein ratio before treatment was predictive of renal response. Immunological remission occurred after 11 treatment courses and was associated with clinical response in 10 of 11 patients. Three patients experienced severe adverse events.ConclusionRTX seems effective and reasonably safe in PLA2R-associated membranous nephropathy with stage 4 or 5 chronic kidney disease. Immunological remission is associated with a good clinical outcome.

Dextran-Sulfate Plasma Adsorption Lipoprotein Apheresis in Drug Resistant Primary Focal Segmental Glomerulosclerosis Patients: Results From a Prospective, Multicenter, Single-Arm Intervention Study.

Background: Focal segmental glomerulosclerosis (FSGS) causes end stage renal disease (ESRD) in significant proportion of patients worldwide. Primary FSGS carries poor prognosis and management of FSGS patients, refractory to standard treatments or resistant to steroids, remains a major challenge. Lipoprotein apheresis is a therapeutic approach for drug resistant primary FSGS and post-renal transplant primary FSGS recurrence.Objectives: To examine the safety and probable benefit at 1, 3, 6, 12, and 24-months following completion of apheresis treatment using Liposorber® LA-15 system in patients with nephrotic syndrome (NS), due to refractory primary FSGS or primary FSGS associated NS, in post renal transplant children.Material and Methods: Prospective, multicenter, single-arm intervention study using Liposorber® LA-15 system. Patients ≤21 years old with drug resistant or drug intolerant NS secondary to primary FSGS with glomerular filtration rate (GFR) ≥60 ml/min/1.73 m2 or post renal transplant patients ≤21 years old with primary FSGS associated NS were included in the study. Each patient had 12 dextran-sulfate plasma adsorption lipoprotein apheresis sessions over a period of 9 weeks. All patients were followed up at 1, 3, 6, 12, and 24-months following completion of treatment.Results: Of 17 patients enrolled, six were excluded from the outcome analysis (protocol deviations). Of the remaining 11 patients, all but one have completed apheresis treatments. Three patients were lost to follow-up immediately after completion of apheresis and excluded from outcome analysis. At one-month follow-up, 1 of 7 patients (14.3%) attained partial remission of NS while 2 of 4 subjects (50%) and 2 of 3 subjects (66.7%) had partial/complete remission at 3- and 6-months follow-up, respectively. One of two patients followed up for 12 months had complete remission and one patient had partial remission of NS after 24 months. Improved or stable eGFR was noted in all patients over the follow-up period.Conclusion: The results of our multicenter study showed improvement in the response rates to steroid or immunosuppressive therapy and induced complete or partial remission of proteinuria in some of the patients with drug resistant primary FSGS. The main limitation of our study is the small number of subjects and high dropout rate.

Thrombin Generation in Nephrotic Syndrome Is Dependent on Remission Status and Hypercholestrolemia

Nephrotic syndrome (NS) is associated with a complex acquired hypercoagulopathy and a strong predilection for venous thromboembolic (VTE) complications. Thromboembolic disease complicates an estimated 27% of adult and 3% of pediatric NS cases. Nonetheless, routine prophylactic anticoagulation for NS remains controversial due to a lack of randomized trials demonstrating safety (bleeding) and efficacy as well as a lack to validated VTE-risk markers. We and others have previously shown that NS disease severity, as determined by proteinuria and serum albumin, is correlated with VTE-risk and may thus be a useful guide to thromboprophylaxis in the future. In animal models we have shown that hypercoagulopathy, as determined by thrombin generation assay (TGA), is proportional to NS severity and others have shown that TGA has predictive value for both incident and recurrent VTE in non-NS patients. We thus sought to determine the relationship between TGA and NS severity in human disease. Standard sodium citrate plasma aliquots (N=150) were obtained from the Nephrotic Syndrome Study Network (NEPTUNE) biorepository. Patients taking anticoagulants or antiplatelet agents were excluded. Correlated phenotypic data for each sample was collected from the NEPTUNE database. The NEPTUNE protocol defined complete NS remission a priori as UP:C &lt;0.3 and partial remission as UP:C &lt;3.5 with concomitant reduction of UP:C by ≥50% from diagnosis. To control for potential pre-analytical confounders which may be present in banked aliquots, an incident NS validation cohort (N=23) was established from whom plasma (collected into sodium citrate supplemented with corn trypsin inhibitor) and urine were analyzed at disease presentation. TGA was performed using the Technothrombin TGA kit and RCLow activator reagent (&lt;3 pM tissue factor and &lt;0.6 mM phospholipid) on 2:1 plasma:buffer dilutions and endogenous thrombin potential (ETP) was calculated as the area under the thrombin activity curve. Plasma albumin levels were determined by the bromocresol purple assay. Univariate linear and backward selection multivariable logistic regression was performed using SAS v9.4. TGA was undetectable in 3 (2%) of the NEPTUNE samples and those samples were excluded from further analysis. Univariate linear regression of ETP on the remaining 147 samples revealed significant relationships with age (B -16), proteinuria (log-urinary protein:creatinine ratio (UP:C); B 490), plasma albumin (B -657), and lipid profile components (e.g. total cholesterol B 2,129). Histologic classification of NS was not associated with ETP. ETP was significantly higher during active disease (no remission) than during complete or partial remission (Figure A). Non-linear regression modeling revealed a polynomial relationship between UP:C and ETP (Figure B) with a nadir ETP at UP:C 0.28. Multivariable modeling revealed that log-Total Cholesterol, log-UP:C (polynomial), Plasma Albumin, and Age were independently predictive of ETP (P values &lt;0.04, respectively; Table). The final multivariable model was highly correlated with ETP (R2=0.35). Similar NS-severity univariate relationships were demonstrated in the validation cohort where log-UP:C (B 853; P&lt;0.01) and plasma albumin (B -1,761; P=0.02) were both correlated with ETP. Proteinuria, plasma albumin, and hyperlipidemia are strongly associated with hypercoagulopathy as assessed by ETP during active NS. Analyzing these NS severity markers and ETP in relation to thrombotic events in future studies may inform their utility to guide the clinical application of thromboprophylaxis for NS patients. Disclosures Kerlin: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding.

MENTOR heralds a new era of therapy for membranous nephropathy.

The MENTOR trial reported that rituximab is superior to ciclosporin for remission of nephrotic syndrome in patients with membranous nephropathy. Rituximab is better tolerated than other treatments but, as up to 40% of patients did not respond to rituximab, alternative immunosuppressive therapies may still be required for a substantial minority of patients.

Urinary apolipoprotein AI in children with kidney disease

Although high-density lipoprotein (HDL) modulates many cell types in the cardiovascular system, little is known about HDL in the kidney. We assessed urinary excretion of apolipoprotein AI (apoAI), the main protein in HDL. We enrolled 228 children with various kidney disorders and 40 controls. Urinary apoAI, albumin, and other markers of kidney damage were measured using ELISA, apoAI isoforms with Western blot, and renal biopsies stained for apoAI. Patients followed in nephrology clinic had elevated urinary apoAI vs. controls (median 0.074μg/mg; interquartile range (IQR) 0.0160-0.560, vs. 0.019μg/mg; IQR 0.004-0.118, p < 0.001). Patients with tubulopathies, renal dysplasia/congenital anomalies of the kidney and urogenital tract, glomerulonephritis, and nephrotic syndrome (NS) in relapse had the greatest elevations (p ≤ 0.01). Patients with NS in remission, nephrolithiasis, polycystic kidney disease, transplant, or hypertension were not different from controls. Although all NS in relapse had higher apoAI excretion than in remission (0.159 vs. 0.0355μg/mg, p = 0.01), this was largely driven by patients with focal segmental glomerulosclerosis (FSGS). Many patients, especially with FSGS, had increased urinary apoAI isoforms. Biopsies from FSGS patients showed increased apoAI staining at proximal tubule brush border, compared to diffuse cytoplasmic distribution in minimal change disease. Children with kidney disease have variably increased urinary apoAI depending on underlying disease. Urine apoAI is particularly elevated in diseases affecting proximal tubules. Kidney disease is also associated with high molecular weight (HMW) apoAI isoforms in urine, especially FSGS. Whether abnormal urinary apoAI is a marker or contributor to renal disease awaits further study.

Circulating anti-phospholipase A2 receptor antibodies as a diagnostic and prognostic marker in Greek patients with idiopathic membranous nephropathy - a retrospective cohort study.

Circulating autoantibodies against phospholipase A2 receptor (anti-PLA2R) are recognized as key elements in the pathogenesis of idiopathic membranous nephropathy. In current clinical practice, they are increasingly gaining attention as novel tools for diagnosis and disease monitoring. We investigated the diagnostic and prognostic utility of anti-PLA2R antibody measurements in Greek patients with biopsy-proven membranous nephropathy. Anti-PLA2R levels were measured in serum samples from 33 patients at diagnosis using ELISA and were associated with treatment outcome. Moreover, serial anti-PLA2R measurements were performed in 15 patients under different clinical conditions and level alterations were correlated with disease activity. Positive anti-PLA2R antibodies at diagnosis were found in 16 of 33 patients (48.5%). Anti-PLA2R levels were independently associated with the achievement of complete remission of nephrotic syndrome after immunosuppressive treatment compared to partial remission (p = 0.02, R2 = 0.265, 95%CI -0.019 to -0.0003). Higher detectable antibody levels at diagnosis were correlated with higher proteinuria levels (r = 0.813, p = 0.0001, 95%CI 0.532 to 0.933) and lower eGFR at the end of follow-up (r = -0.634, p = 0.0083, 95%CI -0.86 to -0.202). Serial antibody measurements during follow-up showed that anti-PLA2R titers were significantly reduced at the end of treatment after complete remission was achieved, remained low under sustained clinical remission, and increased during relapse. Our findings confirm the usefulness of anti-PLA2R measurements in the diagnosis of idiopathic membranous nephropathy. Low levels of anti-PLA2R antibodies at diagnosis are predictive of complete remission of nephrotic syndrome following immunosuppressive treatment. Serial anti-PLA2R measurements correlate well with clinical status throughout the follow-up period and could be used routinely for monitoring of disease activity and treatment planning.

Bioimpedance Resistance Indices and Cell Membrane Capacitance Used to Assess Disease Status and Cell Membrane Integrity in Children with Nephrotic Syndrome.

Background Accumulation of extracellular water (ECW) is a major clinical manifestation of nephrotic syndrome (NS) in children. Bioimpedance spectroscopy (BIS) is a simple, noninvasive technique that reflects body water volumes. BIS can further measure cell membrane capacitance (CM), which may be altered in NS. The aims of the study were to explore how BIS measurements could reflect disease status in NS, while avoiding prediction equations which are often only validated in adult populations. Methods The study involved 8 children (2-10 years) with active NS (ANS group), 5 of which were also studied at NS remission (NSR group), as well as 38 healthy children of similar age (HC group). BIS measurements determined resistances RINF, RE, and RI (reflecting total body water, extracellular water, and intracellular water) and CM. Also resistance indices based on height (H) were considered, RI = H2/R. Results It was found that RE and RINF were significantly lower in the ANS group than in both NSR and HC groups (p < 0.001). Corresponding resistance indices were significantly higher in the ANS group than in the NSR (p < 0.01) and the HC (p < 0.05) groups, in accordance with elevated water volumes in NS patients. Indices of intracellular water were not significantly different between groups. CM was significantly lower in the ANS group than in NSR and HC groups (p < 0.05). Conclusion BIS could distinguish children with active NS from well-treated and healthy children. Studies with more children are warranted.

C5 Convertase Blockade in Membranoproliferative Glomerulonephritis: A Single-Arm Clinical Trial

Primary membranoproliferative glomerulonephritis (MPGN) is a rare glomerulopathy characterized by complement dysregulation. MPGN progresses rapidly tokidney failure when it is associated with nephrotic syndrome. We assessed the effects of C5 convertase blockade in patients with MPGN and terminal complement activation. Prospective off-on-off-on open-label clinical trial. Consenting patients with immune complex-mediated MPGN (n=6) or C3 glomerulonephritis (n=4) with sC5b-9(serum complement membrane attack complex) plasma levels>1,000ng/mL and 24-hour proteinuria with protein excretion>3.5g identified from the Italian Registry of MPGN and followed up at theIstituto di Ricerche Farmacologiche Mario Negri IRCCS (Bergamo, Italy) between March 4, 2014, and January 7,2015. Anti-C5 monoclonal antibody eculizumabadministered during 2 sequential 48-week treatment periods separated by one 12-week washout period. Primary outcome was change in 24-hour proteinuria (median of 3 consecutive measurements) at 24 and 48 weeks. Median proteinuria decreased from protein excretion of 6.03 (interquartile range [IQR], 4.8-12.4) g/d at baseline to 3.74 (IQR, 3.2-4.4) g/d at 24 weeks (P=0.01) and to 5.06 (IQR, 3.1-5.8) g/d (P=0.006) at 48 weeks of treatment, recovered toward baseline during the washout period, and did not significantly decrease thereafter. Hypoalbuminemia, dyslipidemia, and glomerular sieving function improved during the first treatment period. 3 patients achieved partial remission of nephrotic syndrome and all had undetectable C3 nephritic factors before treatment. Mean measured glomerular filtration rate was 69.7±35.2 versus 87.4±55.1 and 75.8±42.7 versus 76.6±44.1mL/min/1.73m2 at the start versus the end of the first and second treatment periods, respectively, among all 10 study participants. Unlike C3, sC5b-9 plasma levels normalized during both treatment periods and recovered toward baseline during the washout in all patients. Single-arm design, small sample size. Eculizumab blunted terminal complementactivation in all patients with immunecomplex-mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in just a subgroup. Registered in the EU Clinical Trials Register with study no. 2013-003826-10.

Characteristics of adverse side effects of corticosteroid therapy in children with nephrotic syndrome and methods of pharmacological correction

Introduction: The article discusses the issues of the long-term glucocorticosteroid therapy in children with nephrotic syndrome that results in severe adverse side effects.&#x0D; Methods: This retrospective study included 89 case reports of patients with nephrotic syndrome, aged 1–18, who received treatment at Voronezh Regional Pediatric Hospital №1 in 1999–2014. The children’s BMI Z-score was calculated from neasured height and weight. The authors considered therapeutical complications revealed through clinical-laboratory and instrumentation examination.&#x0D; Results and discussion: Long-term administration of glucocorticosteroids in patients with steroid-dependent nephrotic syndrome caused overweight and obesity. The patients who had received glucocorticosteroids for 6 months prior to the examination were overweight or obese (78%), had reactive pancreatitis (72%), leukemoid reactions (67%), liver damage (50%), Cushing’s syndrome (44%), chronic gastroduodenitis (33%), hyperglycemia (11%), arterial hypertension (6%), or infectious diseases (6%). The children observed during the period of prolonged remission of nephrotic syndrome had neither overweight, nor obesity or growth failure; signs of chronic gastroduodenitis were observed in 15% of the children.&#x0D; Conclusion: The long-term glucocorticosteroid therapy in children with nephrotic syndrome caused the excess body weight or obesity and gastro-intestinal disorders. So, proton pump inhibitors should be applied simultaneously with glucocorticosteroids to prevent gastro-intestinal disorders

Low aquaporin-2 excretion in the nephrotic syndrome: an escape from the vasopressin regulating effect

PurposeExperimental studies suggest that the nephrotic syndrome is associated with “vasopressin escape”, characterized by low aquaporin-2 (AQP2) expression in the collecting duct despite high vasopressin secretion. We investigated this phenomenon in patients with the nephrotic syndrome.Patients and methodsWe recruited 47 patients with proteinuric kidney disease who were distributed into the following four groups: 1) nephrotic syndrome with kidney dysfunction (n=10); 2) nephrotic syndrome with normal kidney function (n=16); 3) partial remission of nephrotic syndrome (n=10); and 4) minimal proteinuria (n=11). Nine healthy volunteers comprised a control group. Serum copeptin level (as a marker of vasopressin secretion) and urinary AQP2 were measured using ELISA.ResultsNephrotic syndrome was associated with a significant increase in serum copeptin levels compared with those in the other groups (all P<0.05). In patients with nephrotic syndrome and a partial remission of nephrotic syndrome combined, there was more than a ten-fold decrease in the median urinary AQP2 excretion (0.03 ng/mL) compared with healthy volunteers (0.41 ng/mL; P<0.001) and more than a five-fold decrease compared with patients with minimal proteinuria (0.21 ng/mL; P<0.05). Unlike copeptin levels, the median urinary AQP2 excretion in patients with minimal proteinuria also decreased but less significantly than in those with nephrotic syndrome. There was a negative correlation between the urinary AQP2 excretion and daily proteinuria (R=−0.41; P=0.005).ConclusionOur clinical study was the first to demonstrate low AQP2 excretion in nephrotic syndrome that may indicate an escape from the vasopressin regulating effect.

Does cyclophosphamide still play a role in glomerular diseases?

Cyclophosphamide is a prodrug that is converted to inactive carboxy-cyclophosphamide, acrolein and phosphoramide mustard, an agent that adds alkyl groups to oxygen and nitrogen atoms of guanine, one of the four nitrogen bases that form the DNA nucleotides, causing DNA cross-links and introducing DNA breaks. These cytotoxic and mutagenic effects mainly occur in proliferating cells. Repair mechanisms may prevent DNA damage in quiescent cells, but they may be insufficient to contrast the side effects of cyclophosphamide if high doses of the drug are used. Most adverse events are dose- and age-dependent. Phosphoramide mustard can cause bone marrow toxicity, gonadal toxicity, and may favor the development of leukemia, bladder cancer and other types of malignancy. Acrolein can produce hemorrhagic cystitis and even bladder fibrosis when given for prolonged periods. A number of precautional measures should be taken to prevent these untoward events. In particular, long-term administration and high doses of cyclophosphamide should be avoided whenever possible. Today the indications to cyclophosphamide in glomerular diseases are more restricted than in the past, but the drug is still used as a steroid-sparing agent in steroid-sensitive minimal change disease and focal segmental glomerulosclerosis. In membranous nephropathy, cyclophosphamide, alternated or associated with corticosteroids, proved to be beneficial in obtaining remission of nephrotic syndrome and preserving renal function. Cyclophosphamide is considered as a first-line treatment for rapidly progressive glomerulonephritis and the hectic phases of lupus nephritis. In conclusion, cyclophosphamide is a cheap drug that may be useful in a number of glomerular diseases but it may lead to severe side effects. A close monitoring of blood count and clinical conditions, as well as low cumulative doses of cyclophosphamide are strongly recommended when using the drug in patients with renal diseases.

Minimal change disease associated with anti-PD1 immunotherapy: a case report

BackgroundOncologic immunotherapy is a form of therapy intended to reactivate the immune response to tumor cells using agents that modulate immune checkpoints, such as programmed cell death protein 1 and its ligand (PD-1/PD-L), and cytotoxic T-lymphocyte-associated antigen 4. Along with activation of the immune system to tumors, immune-mediated kidney side effects have been reported, most of which are cases of interstitial nephritis. Glomerular disease, however, appears rare.Case presentationHerein, we describe a patient with nephrotic syndrome related to treatment with an anti-PD1 antibody for Hodgkin lymphoma. Following the third dose of anti-PD1 antibody, the patient developed massive proteinuria and nephrotic syndrome. Kidney biopsy showed diffuse podocyte foot process effacement upon electron microscopy, which was consistent with minimal change disease. Corticosteroid treatment yielded full and rapid remission of nephrotic syndrome in 1 month.ConclusionThe present case suggests an association between anti-PD1 therapeutic immune activation and the development of nephrotic syndrome. Given the increasing prevalence of oncologic immunotherapy, patients should be routinely monitored for kidney side effects associated with these agents.

Biochemical bone markers in children with steroid sensitive nephrotic syndrome in remission

Background: Glucocorticoids, the recommended first line treatment of steroid sensitive nephrotic syndrome (SSNS), are notorious for causing osteoporosis. There are very few studies from tropical countries looking at the lasting effects of a short course of glucocorticoids in SSNS. The objective is to study the effect of glucocorticoids and its dose on Vitamin D levels and biochemical markers of calcium metabolism in children with SSNS and to formulate a criterion to administer prophylactic calcium and vitamin D supplementation to such patients.Methods: A cross-sectional case-control study was conducted on 30 children with SSNS in remission and 30 healthy controls. Serum levels of 25 hydroxycholecalciferol [25(OH)D], calcium, phosphorous, albumin, alkaline phosphatase (ALP) and intact parathyroid (PTH) were measured. Total glucocorticoid exposure during the illness was summarized.Results: Children with SSNS had significantly lower height [median-100.00 (interquartile range {IQR}- 14.5) vs. controls [115.50 (17.5)] cm; P= 0.0003. Serum ALP levels was significantly higher in the cases [median 264 (IQR-80.7)] IU/L vs. controls [median 234 (IQR- 132)] IU/L; P= 0.028. Though hypovitaminosis D was universal in the study cohort; children with SSNS had worse Vitamin D status (76.7%) than healthy controls (50%). Levels of serum calcium, phosphorous, vitamin D and PTH were not significantly different between the two groups, nor were they related to total cumulative dose of steroid. Vitamin D levels showed no significant co-relation with number of relapses, age, calcium, phosphate, ALP, or PTH levels.Conclusions: Children with SSNS may benefit from routine measurement of 25 (OH) D and prophylactic supplementation with calcium and Vitamin D.

Mycophenolate mofetil for sustained remission in nephrotic syndrome.

The clinical application of mycophenolate mofetil (MMF) has significantly widened beyond the prophylaxis of acute and chronic rejections in solid organ transplantation. MMF has been recognized as an excellent treatment option in many immunologic glomerulopathies. For children with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) experiencing steroid toxicity, MMF has been recommended as a steroid-sparing drug. Uncontrolled studies in patients with FRNS and SDSN have shown that many patients can achieve sustained remission of proteinuria with MMF monotherapy. Three randomized controlled trials have similarly demonstrated that MMF is beneficial in these patients, but less effective than the calcineurin inhibitors cyclosporin A or tacrolimus. Some, but not all, patients with steroid-resistant nephrotic syndrome (SRNS) may also respond to MMF, usually given in combination with other drugs, with partial or complete remission. There are important limitations to the interpretation and comparability of these studies including study design, sample size, patient selection, clinical endpoints, carry-over effects, and duration of follow-up. In all studies, MMF had relatively few side effects, no nephrotoxicity, or no systemic toxicity. MMF is teratogenic, and contraceptive advice is required in females. There is a poor correlation between MMF dose and mycophenolic acid (MPA) exposure and significant inter- and intra-patient variability in drug pharmacokinetics. A higher estimated MPA-AUC0-12 target range than recommended for pediatric renal transplant recipients is essential to prevent relapses. Therefore, therapy should be guided by drug monitoring to avoid relapses. Further studies are needed to test the efficacy of MMF in inducing remission and, as part of a combination therapy, achieving sustained remission in patients with SRNS.