Full-blown Nephrotic Syndrome Research Articles

#2555 C4d—a novel predictor of the disease progression and treatment failure in primary focal segmental glomerulosclerosis?

Abstract Background and Aims Complement system seems to play a role in the pathogenesis of primary focal segmental glomerulosclerosis (pFSGS) where, due to unpredictable clinical course and outcome, novel prognostic factors are sought. The split product of C4 and tissue marker of complement activation, C4d, is a potential candidate whose prognostic significance was determined in this study. Method Patients >18 years with features consistent with pFSGS (full blown nephrotic syndrome, diffuse podocyte foot processes effacement and exclusion of known causes of FSGS), were recruited from our Hospital registry of kidney biopsies, from 2003 to 2021. Patients with end-stage renal disease (ESRD) defined as eGFR <15 ml/min/1.73 m2 were not included. Every renal biopsy specimen was analyzed by light, immunofluorescence and electron microscopy with additional immunochemistry for C4d performed on paraffin-embedded tissue using monoclonal rabbit antibody (detection system Ventana BenchMark Ultra). Samples with at least one non-globally sclerosed glomerulus (GSG) were examined by two renal pathologists who classified every non-GSG into C4d positive and negative. Based on ratio of C4d+ non-GGS/total N of non-GSG and C4d+ nonsclerotic glomeruli (NSG)/total N of NSG, patients were stratified into two groups: <50% and ≥50%. Primary outcome was defined as composite of ESRD and initial eGFR declining >50%. Failure to meet criteria for at least partial remission at the last follow-up visit according to KDIGO 2021 Guidelines was defined as treatment failure. Numeric variables are shown as median with interquartile range (IQR) and P value <0.05 was considered as significant. Results Relevant data of 58 included patients with renal outcomes are shown in Table. Median follow up was 90.7 (IQR 48-167) months. Patients with ≥50% of C4d+ non-GSG had higher proportion of treatment failure (Table) and worse renal survival (log-rank test, p = 0.006). In multivariate Cox regression analysis, after inclusion of age, sex, initial eGFR and 24-h proteinuria, IFTA, serum albumin and C4d category, only C4d ≥50% (HR = 4.077, 95% CI 1.101-15.09, p = 0.035) and IFTA (HR = 1.052, 95% CI 1.019-1.085, p = 0.002) remained independent predictors of progression to defined endpoint. Likewise, patients with ≥50% of C4d+ NSG/total N of NSG had higher proportion of treatment failure (chi-square, p = 0.03) and worse renal survival (log-rank, p = 0.037). Conclusion C4d deposition is an independent predictor of disease progression, treatment failure and renal survival in pFSGS. Significant influence of NSG-C4d deposition on disease progression may indicate pathophysiological role of the complement system activation in pFSGS independently of the presence of glomerular sclerosis.

#2600 Idiopathic full-house non-lupus nephropathy

Abstract Background and Aims A full-house pattern at immunofluorescence (IF) in kidney biopsies is usually associated with Lupus Nephritis (LN). However, it can be also secondary to other causes, such as infections, or it can idiopathic, without a defined origin. Idiopathic Full House non-lupus Nephropathy (iFH-N) represents a rare entity previously identified in small cohorts of patients, with different clinical features and outcomes. A limited number of the described cases developed overt systemic lupus erythematosus (SLE) during follow up, while renal outcome varied across different studies. A retrospective observational study aimed at evaluating clinical presentation and outcomes of patients with iFH-N in a Tertiary Center has been performed. Long-term renal function and development of overt SLE have been considered as main outcomes of the study. Method All native kidney biopsies performed from January 2012 to December 2022 in our Institution were considered. Full-house pattern was defined as simultaneous positivity for IgG, IgM, IgA, C3 and C1q staining at IF. Inclusion criteria were: age ≥18, full-house pattern at kidney biopsy, patients not meeting criteria for SLE diagnosis according to American College of Rheumatology (ACR) 1997 classification or Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria. Exclusion criteria: diagnosis of SLE, secondary causes of full-house pattern at kidney biopsy. We considered histological, clinical and laboratory features, performed therapies, renal function and SLE development during follow up. Results In the considered period, 2110 patients underwent a native kidney biopsy at our Institution. Of these, 91 patients had a histological finding of full-house nephropathy and were initially included for further evaluation. Of the 91 patients, 84 had received a diagnosis of SLE and were excluded, while 7 did not meet the criteria for a diagnosis of SLE. Two of these 7 were further excluded, having a full house pattern secondary to other conditions. Five patients were finally labelled as iFH-N. At kidney biopsy, all 5 included subjects had a Membranous Nephropathy, with extracapillary proliferation in 2 cases. They were all females, 4 Caucasians (80%), 1 Black (20%). At presentation, mean age was 28.2 years (range 21–40). All had impairment of kidney function, 2 of 5 had a full-blown nephrotic syndrome, 3 of 5 a nephrotic range proteinuria. Mean serum creatinine was 2.1 mg/dl (SD± 0.47), mean eGFR 35.2 ml/min/1.73 m2 (SD ±11), mean proteinuria 7.1 gr/24 h (SD ±3.3). Antinuclear antibodies (ANA) were negative in 4 of 5 patients; anti-dsDNA, anti-extractable nuclear antigens (ENAs) and antiphospholipid antibodies were negative in all subjects; slightly low C3 was present in 3 of 5 subjects. All patients received immunosuppressive therapy, including high dose intravenous (iv) steroids in association with cyclophosphamide (CYC) or mycophenolate mofetil, or Intensified B Cell Depletion Protocol (i.e. iv steroids + CYC and Rituximab). Mean follow-up from the time of kidney biopsy was 7.4 year (SD ± 2.4) (range 3–10 years). During follow up, 4 patients (80%) developed end stage renal disease (ESRD) needing renal replacement therapy, 3 of them within 24 months after presentation. The two patients with crescents had a severe prognosis, starting dialysis within 10 months after presentation. The fifth patient developed chronic kidney disease stage 4. One patient formally developed an ACR negative, SLICC positive SLE two years after presentation, with new positivity for ANA and anti-dsDNA antibodies at high titer and low C3, in addition to renal involvement. Conclusion All patients with iFH-N had similar presentation, being all young females, with a Membranous Nephropathy, nephrotic proteinuria and impairment of kidney function. They all had an aggressive form of kidney disease, refractory to different regimens of immunosuppression and with poor long-term renal outcome. Only one case developed SLE on the long term, although without systemic signs. The relationship between idiopathic full-house nephropathy and SLE remains controversial.

A Case of Fibrillary Glomerulonephritis – When You Least Expect It

ABSTRACT Malignancies can be associated with a wide range of glomerular diseases, with each malignancy having a predilection for a particular glomerular disease. Fibrillary glomerulonephritis (FGN) is usually associated with paraproteinemia and commonly presents as nephrotic range proteinuria with or without the full-blown nephrotic syndrome. Here, we report the case of a young male with left flank pain, found to have left adrenal adenoma, incidentally detected to have microscopic hematuria and nonnephrotic proteinuria whose renal biopsy done during adrenalectomy showed FGN. Indeed, this case demonstrates an unexpected diagnosis with an unusual presentation in the background of an uncommon malignancy. Although difficult to establish causation, it can be considered a unique case of adrenal adenoma-associated FGN.

#3512 GLOMERULOPATHIES DURING PREGNANCY: A TEN-YEAR SINGLE CENTER EXPERIENCE

Abstract Background and Aims Literature regarding pregnancy management and outcomes in women with glomerulopathies is still sparse. Specific guidelines for each glomerulopathy are still lacking which impairs a more homogeneous approach. The authors describe the multidisciplinary approach and the outcomes of pregnant women with primary and genetic glomerulopathies. Method Retrospective observational study in which the authors reviewed maternal, obstetric and perinatal outcomes in pregnant women with primary and genetic glomerulopathies surveilled at our nephro-obstetric clinic from 2011 to 2021. Results We evaluated 23 gestations in 20 patients (two pregnancies still ongoing). Mean age was 32.4±5.4 years (18-41), 17 women were caucasian, 3 black African, 10/23 nulliparous and 5/20 had chronic hypertension. Mean baseline SCr was 0.8±0.3mg/dl (0.5-1.8) and proteinuria was 1360±2199.6 mg/day (150-8615), with 13/6/2 patients being on CKD stage 1/2/3, before pregnancy, respectively (unknown in 2 patients). The most frequent CKD etiologies were IgA nephropathy (6/20), Focal Segmental Glomerulosclerosis (FSGS; 3/20) and Membranous nephropathy (2/20). Exposure to teratogenic therapy during the 1st trimester occurred in 5/23 gestations with a mean exposure of 7.0±3.6 weeks. De novo proteinuria and worsening proteinuria occurred in 3/23 and 16/23 patients, respectively, with full blown nephrotic syndrome in 4/23 patients. Renal function deteriorated in one patient (CKD G3). Kidney biopsy was performed in 1/20 and 3/20 patients during and post pregnancy, revealing IgA Nephropathy (2/20, 1 with superimposed FSGS), C3 glomerulonephritis (1/20) and FSGS (1/20). Genetic diagnosis was done during/post pregnancy in 3/1 patients. Aspirin and LMWH were started in 17/23 and 4/23 gestations, respectively. Immunosuppression consisted of cyclosporin or tacrolimus with or without low dose prednisolone in 6/23 patients with partial and complete remission in all patients. De novo and worsening hypertension occurred in 2/23 and 3/23 gestations, during the 3rd trimester. Preeclampsia developed in 1 patient at 32 weeks. Fetus malformation (trisomy 21) and severe nephrotic syndrome led to pregnancy termination during the 1st trimester in two pregnancies. Cesarean delivery was performed in 5 gestations mainly due to pelvic position. Mean gestation time was 38.9±2 weeks. There was one preterm delivery due to preeclampsia. Mean birth weight was 3076.6±630.7 mg (1500-3850), with 3 newborns having low birth weight (<2500g). Apgar scores at 1/5/10 minutes were 9/10/10, respectively. Neonatal intensive care was needed in 1 newborn. Conclusion In our series, glomerulopathies with proteinuria or nephrotic syndrome were not associated with poor renal and perinatal outcome, with only one patient developing PE and renal function deterioration, probably associated to with CKD stage 3. In patients with nephrotic syndrome, immunosuppression with calcineurin inhibitor and low dose prednisone was associated with complete or partial remission in all patients.

Full-Blown Nephrotic Syndrome in a Fully Vaccinated Woman Following COVID-19 Infection

Full-Blown Nephrotic Syndrome in a Fully Vaccinated Woman Following COVID-19 Infection

MO108: Paraneoplastic Nephrotic Syndrome in a Man with Breast Cancer

Abstract BACKGROUND Nephrotic syndrome is associated with many solid tumours and haematologic malignancies. Membranous nephropathy (MN) is the most commonly reported paraneoplastic glomerulonephritis; about 10% (rate 5–20%) of adults with MN have been reported to have a malignancy [1]. Less frequently, minimal change disease, focal segmental glomerular sclerosis, membranoproliferative and crescentic glomerulonephritis, IgA nephropathy [1] and thrombotic microangiopathy [2] have been associated with cancer. Differentiating primary from secondary glomerular disease in patients with malignancy can be difficult. The probability of a secondary form is higher when the appearance of proteinuria or nephrotic syndrome precedes by few months or develops within a year of cancer diagnosis. The suspicion of paraneoplastic nephropathy is even stronger when tumour remission is associated by significant fall in proteinuria and when recurrence of malignancy is followed by the development of clinical glomerular disease. Solid tumour most commonly associated with glomerular diseases (mainly MN) is lung cancer, followed by prostate and colorectal cancer. Paraneoplastic glomerular diseases are rarely linked to breast cancer. In two reviews, breast cancer was reported only in 3% (5 out of 159 patients) [1] and 8% (6 out of 85 patients) of patients with MN and solid tumours. Breast cancer is the most common malignancy in women, while it is a rare disease in men. Male breast cancers account for less than 1% of all diagnosed cases, and the mean age is usually over 60 years [1]. METHODS We report the case of a breast cancer in a man associated with a paraneoplastic nephrotic syndrome. A 76-year-old man was managed at our renal department since 2016 for chronic kidney disease. He was overweight and affected by non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease. Since 2016 to December 2020, he had stable renal function with serum creatinine levels ranging from 2.5 to 3.0 mg/dL and a normal urinary protein excretion rate (100–150 mg/24 h). In March 2021, the patient developed a right periareolar breast swelling, pain and erythema with yellowish nipple discharge. In the same period, a full-blown nephrotic syndrome with heavy proteinuria (8 g/24 h) was observed, and serum creatinine increased to 3.5–4.0 mg/dL. Immunological blood tests were negative, including anti-PLA2R and anti-THSD7A antibodies. A kidney biopsy could not be performed due to bilateral renal cysts. Mammogram examination and ultrasound imaging revealed ductal ectasia and microscopic calcifications at the site of right breast lesion, so a diagnosis of cancer was made. RESULTS In September 2021, the patient underwent radical right mastectomy and histopathological examination confirmed early-stage breast cancer (pT1a, pN0, Mx R0, ER 100%, PgR 0, Ki67 5%, CerbB2 neg). In the following month, the 24-h urinary protein excretion markedly reduced to 1.4 g and the nephrotic syndrome resolved completely, confirming its secondary origin. CONCLUSIONS Paraneoplastic nephrotic syndrome is a rare complication of cancer. Its recognition and detection of an undiagnosed malignancy could be life-saving. To our knowledge, this is the first case reported in literature of paraneoplastic nephrotic syndrome in a man affected by breast cancer.

SAT-429 CMV-ASSOCIATED CONGENITAL NEPHROTIC SYNDROME: CORRELATION OF CLINICAL, HISTOPATHOLOGICAL AND GENETIC FINDINGS

Congenital nephrotic syndrome (cNS), defined by onset during the first three months of life, is a rare clinical disorder with traditionally poor renal outcome. It is caused by homozygous or compound heterozygous mutations of a growing number of genes affecting podocyte and/or glomerular basement membrane integrity, with or without syndromic features. Other potential etiologies include antenatal or perinatal infections, or (other) systemic disorders. Case description and systematic review of the literature in PubMed using the key words "CMV", "congenital” or "infant", and "nephrotic” or "glomerulonephritis". This report describes an ex-preterm baby who had been referred at two weeks corrected gestational age for suspected surgical abdomen in view of progressive abdominal distention, scrotal edema and vomiting. The patient was found to have full-blown nephrotic syndrome with urine protein-to-creatinine ratio of > 6 g/g, hypoalbuminemia <10 g/L, hypercholesterolemia and anemia, and elevated liver transaminases. He had syndromic features. Diagnostic workup revealed an active CMV infection, based on CMV-specific IgM and positive CMV PCR from blood and urine. Routine pregnancy screen for intrauterine infections had been negative. Subsequent maternal diagnostic revealed high maternal anti-CMV IgG (IgM negative) and positive CMV PCR. The infant’s kidney biopsy showed focal mesangial proliferation and sclerosing glomerulonephritis with cellular or fibro-cellular crescents in less than 5% of glomeruli, while global or segmental sclerosis associated with older fibrous crescents was noted in 10% of glomeruli, in addition to interstitial fibrosis and tubular atrophy. Routine immune fluorescence was negative. Electron microscopy revealed diffuse podocyte foot process effacement, but no immune complexes or endothelial tubule-reticular inclusions. Infiltrating (interstitial) lymphocytes stained positive for CD3 and CD20, respectively. Results of the genetic mutation screen are pending. After 6 weeks of treatment with valganciclovir, the CMV PCR has become negative, but the infant continues to demonstrate severe proteinuria and hypoalbuminemia. Review of the available literature reveals an important overlap between cNS due to known monogenic causes and CMV infection. Although the number of defined cases in the literature is scarce, we noted divergent histopathological features in CMV-associated cNS, dependent on the presence or absence of cognate genetic mutations as shown in the Table. CMV is a rare cause of nephrotic syndrome presenting soon after birth. Screening for relevant mutations is essential since congenital infections can complicate or mask an underlying genetic etiology leading to the failure of CMV-directed antiviral therapy and poor renal outcome.

Alport syndrome and pregnancy: a case series and literature review.

To assess pregnancy outcome in women with Alport syndrome and the impact of pregnancy on the disease progression. We describe one of the largest series of pregnancies in Alport syndrome. Seven pregnancies of six women were monitored by a multidisciplinary team of nephrologists and gynecologists. After delivery, patients were followed for at least 3years. We compare our results with those in the literature. Pregnancy course was uneventful in the patient with isolated microscopic hematuria. In the other cases, all presenting mild proteinuria at conception, some complications occurred. Proteinuria worsened during the last trimester, reaching nephrotic ranges in five out of six pregnancies and was associated with fluid overload leading to hospitalizations and early delivery. The majority of the newborns had a low birth weight. The two patients with arterial hypertension at conception and twin pregnancy developed pre-eclampsia and renal function deterioration persisted after delivery. The one with pre-pregnancy renal dysfunction reached end-stage renal disease. In the other patients, in which renal function and blood pressure were and remained normal, proteinuria improved after delivery and no signs of disease progression were recorded at last observation. Our observations suggest that Alport syndrome should be considered a potential risk factor for pregnancy in proteinuric patients due to the development of pre-eclampsia, renal function deterioration, and/or full-blown nephrotic syndrome that results in anasarca, slowing of fetal growth and pre-term delivery. Thus, all women with Alport syndrome should receive pre-conceptional counseling and be kept in close follow-up during pregnancy.

Full blown nephrotic syndrome due to unilateral obstruction of the uretero-pelvic junction

Full blown nephrotic syndrome due to unilateral obstruction of the uretero-pelvic junction

What are we missing in the clinical trials of focal segmental glomerulosclerosis?

Focal segmental glomerulosclerosis (FSGS) is a lesion and not a disease. This conundrum is the crux of controversies regarding interventions to alter its natural history. In the broadest sense, the lesion can be primary (idiopathic), or secondary to a process originating outside the kidneys or to a genetic mutation. The organ-based target is the podocyte, and the mechanisms responsible for the podocytopathy are numerous and diverse. Recurrence of primary FSGS in renal allografts provides the best evidence for the existence of a circulating factor or factors, the nature of which remains uncertain. The separation of primary from secondary FSGS clinically and pathologically is challenging, but full-blown nephrotic syndrome and diffuse (universal) foot process effacement are strong signals for a primary form of FSGS. It is imperative that clinical trials designed to investigate therapeutic strategies for patients with a lesion of FSGS pay careful attention to the separation of primary from secondary forms of FSGS. This critical review provides a rationale and a process for helping to ensure that this is accomplished, such that clinical trials provide useful information and treatment responsiveness applicable to the primary forms of FSGS.

Subclinical pulmonary congestion is prevalent in nephrotic syndrome.

In patients with nephrotic syndrome (NS), the lung is considered an organ protected from the risk of edema. However, data on objectively measured lung water in NS patients is lacking. Here we measured lung water by an ultrasound (US) technique as well as by transthoracic impedance in 42 asymptomatic patients with active NS, in 14 stage G5D CKD patients on chronic hemodialysis, and in 21 healthy individuals. In patients with active NS, the median number of US-B lines (a metric of lung water) after 5 min in a supine position was significantly higher (12; interquartile range: 7-25) compared with that in healthy individuals (4; 2-9) but similar to that in hemodialysis patients (23; 10-39). The difference between NS patients and healthy individuals was significantly amplified (16; 10-35 vs. 4; 2-9) after 60 min of supine resting and significantly attenuated after 5 min of standing (10; 7-25 vs. 3; 1-6). Posture-dependent changes in lung water in patients with active NS were significantly accentuated compared with both hemodialysis patients and healthy individuals. After NS remission, the number of US-B lines was significantly reduced to 5 (4-18) at 5 min and to 6 (5-22) at 60 min approaching the normal range. Lung congestion in patients with active NS was confirmed by transthoracic impedance. Thus, asymptomatic pulmonary congestion is pervasive in patients with NS. A clinical trial is needed to assess the utility of lung US for the management of patients with NS.

Glomerular diseases: membranous nephropathy--a modern view.

Membranous nephropathy (MN) is an autoimmune disease usually associated with a nephrotic syndrome and it may progress to ESRD in the long term. Its etiology is often unknown (idiopathic MN), whereas other cases have a recognizable etiology (secondary MN). In idiopathic MN, the glomerular lesions are mainly caused by autoantibodies against a podocyte membrane protein, the M-type of phospholipase A2 receptor 1. The natural course of idiopathic MN is quite varied with spontaneous complete or partial remissions a relatively common occurrence. Patients with asymptomatic non-nephrotic proteinuria seldom progress and need only conservative management. Those with persistent full-blown nephrotic syndrome and those with declining renal function are candidates for specific treatment with any of several regimens. Cyclical therapy with alternating monthly intravenous and oral glucocorticoids combined with a cytotoxic agent can induce remission and preserve renal function in the long term. Cyclosporine or tacrolimus can induce remission, but relapses are frequent after the drug withdrawal. Mycophenolate mofetil monotherapy seems to be ineffective, but may be beneficial when administered together with steroids. The experience with adrenocorticotropic hormone, natural or synthetic, is limited to a few studies with short-term follow-up, but high rates of remission can be seen after prolonged treatment. A high rate of remission and good tolerance have also been reported with rituximab. Patients with moderate renal insufficiency may also benefit from treatment, but at a price of frequent and serious side effects. With these limitations in mind, idiopathic MN may be considered a treatable disease in many patients.

Hyperaldosteronemia and Activation of the Epithelial Sodium Channel Are Not Required for Sodium Retention in Puromycin-Induced Nephrosis

Edema and ascites in nephrotic syndrome mainly result from increased Na+ reabsorption along connecting tubules and cortical collecting ducts (CCD). In puromycin aminonucleoside (PAN)-induced nephrosis, increased Na+ reabsorption is associated with increased activity of the epithelial sodium channel (ENaC) and Na+,K+-ATPase, two targets of aldosterone. Because plasma aldosterone increases in PAN-nephrotic rats, the aldosterone dependence of ENaC activation in PAN nephrosis was investigated. For this purpose, (1) the mechanism of ENaC activation was compared in nephrotic and sodium-depleted rats, and (2) ENaC activity in PAN-nephrotic rats was evaluated in the absence of hyperaldosteronemia. The mechanism of ENaC activation was similar in CCD from nephrotic and sodium-depleted rats, as demonstrated by (1) increased number of active ENaC evaluated by patch clamp, (2) recruitment of ENaC to the apical membrane determined by immunohistochemistry, (3) shift in the electrophoretic profile of gamma-ENaC, and (4) increased abundance of beta-ENaC mRNA. Corticosteroid clamp fully prevented all PAN-induced changes in ENaC but did not alter the development of a full-blown nephrotic syndrome with massive albuminuria, amiloride-sensitive sodium retention, induction of CCD Na+,K+-ATPase, and ascites. It is concluded that in PAN-nephrosis, (1) ENaC activation in CCD is secondary to hyperaldosteronemia, (2) sodium retention and induction of Na+,K+-ATPase in CCD are independent of hyperaldosteronemia, and (3) ENaC is not necessarily limiting for sodium reabsorption in the distal nephron.

Should we biopsy kidneys of patients post-liver transplant?

Thirty days after orthotropic liver transplantation, a 52-year-old Hispanic male developed full-blown nephrotic syndrome. Although the patient was posttransplantation, he underwent a kidney biopsy under real-time ultrasound guidance. The pathological specimen revealed membranous nephropathy. A change in the immunosuppressive regimen resulted in a rapid decrease in urinary protein excretion, leading to resolution of the nephrotic syndrome. We report this case to illustrate the precautions that need to be taken when liver transplant patients require a kidney biopsy.

ICRF-187 (dexrazoxan) protects from adriamycin-induced nephrotic syndrome in rats.

Reactive oxygen species produced during metabolism of adriamycin are purported to play an important role in the pathogenesis of experimental adriamycin nephropathy in rats. ICRF-187 (dexrazoxan, Cardioxan), an iron chelator, has been shown to inhibit adriamycin-induced formation of hydroxyl radical and to decrease adriamycin cardiotoxicity in oncological patients. The aim of our study was to assess the putative protective role of ICRF-187 in adriamycin nephropathy by evaluating the possible participation of free radicals in its pathogenesis. We examined five experimental groups. Group A, received a single dose of adriamycin (5 mg/kg bw i.v.), group CA was given a single dose of ICRF-187 (100 mg/kg bw i.v.) before adriamycin administration, group CCA received a single dose of ICRF-187 (100 mg/kg bw i.v.) before adriamycin administration followed by three weekly intraperitoneal injections (100 mg/kg bw) ICRF-187. Group CC received one dose of ICRF-187 (100 mg/kg bw i.v.) followed by three weekly intraperitoneal injections of ICRF-187, and group N served as control receiving saline. Common biochemical parameters, malondialdehyde (MDA) and antioxidant enzymes (glutathione peroxidase--GPx and superoxide dismutase--SOD) in blood and kidney homogenates were measure and histology of the kidney was studied after the rats were sacrificed. Full-blown nephrotic syndrome developed after 3 weeks only in A rats. Nephrotic syndrome was completely prevented in all ICRF-187 treated rats (CA, CCA). Proteinuria was significantly increased in A rats (108.2 + 48.4 mg/l of glomerular filtrate) compared with CA (12.4 + 6.8 mg/l, P < 0.0001) and with N (6.1 + 3.5 mg/l, P < 0.0001). Total MDA in erythrocytes was significantly increased only in A rats (1.7 + 0.3 micromol/l) and was completely normalized by ICRF-187 in CA (1.1 + 0.2 micromol/l, P < 0.001). Total TBARS and MDA in kidney homogenates were significantly elevated in groups with repeated administration of ICRF-187 (CC and CCA rats) compared to N, CA, A groups. Activity of GPx and SOD in kidney homogenate and in erythrocytes was not significantly increased by ICRF-187 in adriamycin treated rats. Histologic changes in A rats resembled minimal change nephropathy with fusion of foot processes and hyaline casts in tubules. There was only minimal mesangial proliferation and perivascular mast cell infiltrates in all groups of ICRF-187-treated rats. We conclude that ICRF-187, probably by chelation iron, completely protected rats from adriamycin-induced nephrotic syndrome. It supports the role of iron-mediated reactive oxygen species in the development of this type of glomerular injury. However, repeated administration of ICRF-187 alone is able to increase parameters of oxidative stress in the kidney.

Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976–1979 and 1995–1997

Data compiled during the 1970s and early 1980s indicated that during these periods, membranous nephropathy was the most common cause of unexplained nephrotic syndrome in adults, followed in order of frequency by minimal-change nephropathy and focal segmental glomerulosclerosis (FSGS). However, we and others recently reported an increase in the incidence of FSGS over the past two decades, and the number of cases of FSGS diagnosed by renal biopsies in these centers now exceeds the number of cases of membranous nephropathy. Nonetheless, as a substantial fraction of patients with FSGS do not have the nephrotic syndrome, it remained unclear as to what extent the relative frequencies of FSGS and other glomerulopathies as causes of the nephrotic syndrome have changed over this time. To address this concern, we reviewed data from 1,000 adult native kidney biopsies performed between January 1976 and April 1979 and from 1,000 biopsies performed between January 1995 and January 1997, identified all cases with a full-blown nephrotic syndrome of unknown etiology at the time of biopsy, and compared the relative frequencies with which specific diseases were diagnosed in these latter cases between the two time intervals. The main findings of this study were that, first, during the 1976 to 1979 period, the relative frequencies of membranous (36%) and minimal-change (23%) nephropathies and of FSGS (15%) as causes of unexplained nephrotic syndrome were similar to those observed in previous studies during the 1970s and early 1980s. In contrast, from 1995 to 1997, FSGS was the most common cause of this syndrome, accounting for 35% of cases compared with 33% for membranous nephropathy. Second, during the 1995 to 1997 period, FSGS accounted for more than 50% of cases of unexplained nephrotic syndrome in black adults and for 67% of such cases in black adults younger than 45 years. Third, although the relative frequency of nephrotic syndrome due to FSGS was two to three times higher in black than in white patients during both study periods, the frequency of FSGS increased similarly among both racial groups from the earlier to the later period. Fourth, the frequency of minimal-change nephrotic syndrome decreased from the earlier to the later study period in both black and white adults. Fifth, the relative frequency of membranoproliferative glomerulonephritis as a cause of the nephrotic syndrome declined from the 1976 to 1979 period to the 1995 to 1997 period, whereas that of immunoglobulin A nephropathy appeared to increase; the latter accounted for 14% of cases of unexplained nephrotic syndrome in white adults during the latter study period. Finally, 10% of nephrotic adults older than 44 years had AL amyloid nephropathy; none of these patients had multiple myeloma or a known paraprotein at the time of renal biopsy.

Recurrent Hereditary Polyserositis or Familial Mediterranean Fever: An Overview

The etiology and pathogenesis of recurrent hereditary polyserositis (RHP) remain undetermined. There is a good evidence for a genetic basis (transmission being by a recessive Mendelian mode of inheritance), but not all cases have a family history and an infective (or other environmental) components has not been excluded. The marked variation in presentation and complications (in particular the prevalence of amyloid deposition) in different series suggests that this might not be a homogeneous entity. Vascular involvement is a basic prerequisite for the periodic attacks, and evidence for transient immunological abnormalities is incontrovertible. There are no reliable diagnostic techniques. Colchicine is of value in treatment, but its mode of action is unclear. More macro- and microepidemiological studies are required and will be of paramount importance. Clinical observations and molecular genetic studies should address the possibility that two or more immunological or metabolic defects might be interwoven; why for example do only some affected groups develop AA amyloidosis? Simple, non-invasive diagnostic tests are required for the uncomplicated disease and also for the presence of amyloid deposition. Preventive strategies might eventually involve genetic engineering techniques, but in the immediate future, education of doctors and other health care workers - to raise the "index of awareness" of RHP, in order that colchicine treatment can be commenced early in the disease - forms an important strategy. Colchicine therapy is not without complications and an alternative chemotherapeutic agent should be sought.

Minimal-Change Nephropathy and Malignant Thymoma

A 56-year-old man had fever, precordial pain, and a mediastinal mass. The mass disappeared two months later and the patient remained asymptomatic for 2 1/2 years. At that time a full-blown nephrotic syndrome developed, with minimal-change glomerulopathy. The chest x-ray film showed the reappearance of a giant mediastinal mass. On biopsy of the mass, malignant thymoma was diagnosed. Association between minimal-change disease and Hodgkin's disease is well known, while the association with malignant thymoma has not been previously reported. The relationship between malignant thymoma and minimal-change disease is discussed, and a possible pathogenic mechanism involving cell-mediated immunity is proposed.