Persistent Nephrotic-range Proteinuria Research Articles

#3741 A CASE OF PODOCYTIC INFOLDING GLOMERULOPATHY WITH DIABETES MELLITUS, NEPHROTIC RANGE PROTEINURIA AND POSITIVE ANTI-PLA2R IN SERUM

Abstract Background and Aims Podocytic infolding glomerulopathy (PIG) is a rare glomerular abnormality which was first proposed as a new disease entity in 2008. It is characterized by glomerular basement membrane (GBM) bubbling viewable by light microscopy, due to extensive trapping of podocytic cytoplasm fragments and cell membrane projections within the GBM. Electron microscopy reveals podocyte infolding and invagination into the glomerular basement membranes (GBMs). Most of the cases reported worldwide, indicate that PIG usually co-exists with autoimmune diseases. In this case we present a diabetic patient with no other autoimmune disease in his medical history, whose biopsy was characterized as PIG. Method A 60-year-old Caucasian man with a 5-year history of type II diabetes mellitus, hyperlipidemia, hypertension, hyperuricemia and benign colon polyps, was noted by his family physician to have proteinuria. He had been treated with an angiotensin II receptor blocker, statin, and allopurinol for 5 years and he was well regulated. At the point of admission, his 24-h urine collection showed 4,5gr of urine protein. His creatinine at the time was normal (0,89mg/dl), no hypoalbuminemia, no edema or deregulation of hyperlipidemia was noted. His fundoscopy at this point had no diabetic lesions. In the immunological work up, we found normal values of autoantibodies ANA, anti-dsDNA, anti-ENA, complement screening C3, C4, serum and urine protein electrophoresis - immunofixation. Everything was within normal limits except from serum autoantibodies to Phospholipase A2 Receptor of podocytes which was tested with ELISA and valued 35 RU/mL (<20RU/mL). In the following 9 months his proteinuria remained at the same levels. Due to the persistent nephrotic range proteinuria (>3.5gr/24h) a kidney biopsy was performed. Biopsy was evaluated under light microscope (histochemistry for Congo-Red and immunohistochemistry for C4d, PLA2R and DNAJB9 included), immunofluorescence and electron microscope. Results The renal biopsy included 8 glomeruli, 3 of them globally sclerosed (37.5%), the rest enlarged with mild to moderate mesangial matrix increase and thickening of the GBMs, without spikes, pin holes or reduplications. Immunohistochemistry for C4d, PLA2R and DNAJB9 was negative. Immunofluorescence revealed nothing noticeable (no staining of IgG, IgA, IgM, C3, C1q, C4, κ-λ chains) apart from a moderate linear albumin staining. Without electron microscopy the whole picture was rather reminiscent of mild to moderate lesions of diabetic nephropathy. On electron microscopy, no classical electron-dense deposits were found. Effacement of podocytes’ foot processes was multi-segmental. More importantly, podocytic cytoplasmic processes invaginating into the GBMs were observed, accompanied by scattered endomembranous, partially microspherular microstructures, sometimes with adjacent unclear small pyknotic areas. The biopsy report concluded that although light microscopy and immunofluorescence findings could indicate diabetic nephropathy, the electron microscopy lesions suggest the diagnosis of PIG. Conclusion To our knowledge, this is the first reported case with PIG and anti-PLA2R antibodies detected in the serum, without clear histological evidence of membranous nephropathy. Our patient was diabetic for five years with no diabetic lesions in fundoscopy. Although PIG has been reported mainly in the context of autoimmune diseases, the coexistence with diabetes or its possible role in PIG's pathogenesis has not been addressed. The treatment of this peculiar morphologically disease, still remains an open query for physicians.

Low- Versus High-dose Cyclophosphamide in Class III/IV Lupus Nephritis: A Retrospective Study from South Asia.

The comparative efficacy of low-dose cyclophosphamide (LD-CYC) and high-dose cyclophosphamide (HD-CYC) for treatment of lupus in South Asians is not well established. We aimed to compare treatment outcomes in South Asian patients with class III and IV lupus nephritis treated with either regimen. This was a single-center, retrospective study conducted in Sri Lanka. Patients with biopsy-proven class III or IV lupus nephritis were recruited. The HD-CYC group was defined as having received ≥6 doses of 0.5-1 g/m2 cyclophosphamide (CYC) followed by quarterly doses. The LD-CYC group was defined as having received six doses of 500 mg CYC at two-weekly intervals. The primary outcome was treatment failure defined as persistent nephrotic range proteinuria or renal impairment at 6 months. Sixty-seven patients were recruited (HD-CYC 34, LD-CYC 33), all South Asian ethnicity. The HD-CYC group had received treatment between 2000 and 2013, and the LD-CYC group from 2013 onward. The HD-CYC and LD-CYC groups had 30/33 (90.9%) and 31/34 (91.2%) females, respectively. Nephrotic syndrome and nephrotic range proteinuria on presentation were seen in 22/33 (67%) and 20/32 (62%) in the HD-CYC and LD-CYC groups, respectively, and renal impairment was seen in 5/33 (15%) of the HD-CYC group and 7/32 (22%) of the LD-CYC group (P > 0.05). Treatment failure and complete or partial remission occurred in 7/34 (21%) and 28/34 (82%), respectively, of HD-CYC and 10/33 (30%) and 24/33 (73%), respectively, of LD-CYC (P > 0.05). Adverse events rates were similar. This study suggests that LD-CYC and HD-CYC induction is comparable in South Asian patients with class III and IV lupus nephritis.

The quantifying relationship between the remission duration and the cardiovascular and kidney outcomes in the patients with primary nephrotic syndrome

Background Patients with persistent nephrotic-range proteinuria have a high risk of kidney dysfunction and cardiovascular events. Recently, the maintenance of proteinuria remission has been demonstrated to reduce the risk of kidney endpoint. However, the effect of remission duration on cardiovascular outcomes remains unclear. Methods This study enrolled 982 patients with primary nephrotic syndrome who had achieved clinical remission. Remission duration was defined as the maintenance time (months) of the first remission. Arteriosclerotic cardiovascular disease (ASCVD) and kidney dysfunction (ESKD or eGFR reduction >50%) were the endpoints. Survival curves, Cox regression models, restricted cubic spline analysis were used and the cutoff time points were determined. Results During the 38.3 months of follow-up, 161 (16.4%) patients developed ASCVD (51.3 per 1000 patient-years) and 52 (5.3%) patients developed kidney dysfunction (15.3 per 1000 patient-years). Multivariate analysis showed that remission duration was an independently protective factor to ASCVD, in which each one-year extension associated with a 15% reduction of the risk (HR, 0.854; 95% CI, 0.776 ∼ 0.940, p = .001). The initial time point was seven months for remission to present the protective effect to ASCVD and the maximum time point was 36 months. Remission duration was also an independently protective factor to kidney dysfunction. This effect was shown from the beginning of remission and reached the maximum at 26 months. Conclusions The maintenance of proteinuria remission was crucial for the improvement of cardiovascular and kidney outcomes in nephrotic syndrome patients.

Mesangial sclerosis in a patient with type 1 diabetes following simultaneous pancreas-kidney transplantation despite maintenance of normoglycemia: a case report

BackgroundSimultaneous pancreas-kidney transplantation is considered a curative treatment for type 1 diabetes complicated by end-stage kidney disease. We report herein a case of mesangial sclerosis in a patient who underwent successful kidney-pancreas transplantation despite well-controlled glucose and excellent pancreatic allograft function.Case presentationA 76-year-old type 1 diabetic man who underwent a simultaneous pancreas-kidney transplantation 19 years prior presented with persistent nephrotic range proteinuria although creatinine was at his baseline (normal) level. Hemoglobin A1c and fasting glucose were well controlled without the use of insulin or oral antihyperglycemic agents. Serum lipase and amylase were within the reference range and there was no evidence of donor-specific antibodies. Kidney allograft biopsy was performed to evaluate proteinuria and showed diffuse capillary loop thickening and diffuse moderate to severe mesangial sclerosis resembling diabetic nephropathy.ConclusionsThis case demonstrates a case of mesangial sclerosis resembling diabetic nephropathy in a patient with good glucose control after simultaneous pancreas-kidney transplantation with excellent pancreatic allograft function.

Later Response to Corticosteroids in Adults With Primary Focal Segmental Glomerular Sclerosis Is Associated With Favorable Outcomes

IntroductionGuidelines advise initial therapy with corticosteroids (CSs) in patients with presumed primary focal segmental glomerular sclerosis (pFSGS). Many patients do not achieve complete remission (CR) after 8 or 16 weeks. Although these patients are considered steroid resistant, clinical outcomes are ill defined.MethodsA retrospective cohort study of patients with pFSGS who were referred between January 1995 and December 2014. Data of clinical presentation until last follow-up were collected from patient records.ResultsA total of 51 patients (median age 47 years, 20 female/31 male) were included (median follow-up 7.1 years). There were 10 patients who achieved partial response (PR) at 8 weeks. High-dose CS monotherapy was continued for a median of 17 weeks (interquartile range [IQR] 11–21 weeks) (total duration 56 weeks [IQR 28–83 weeks]). With CSs, the cumulative incidence of CR + PR was 18% and 35%, respectively. Of 24 patients with persistent nephrotic-range proteinuria, 22 received additional immunosuppressive (IS) therapy, resulting in CR in 3 (14%) and PR in 11 patients (50%). A decrease of >20% of proteinuria at 8 weeks predicted response. In addition, 8 patients (36%) were considered primary nonresponders. A genetic cause was found in 2 patients. Proteinuria at end of follow-up was 1.2 g (IQR 0.4–3.0 g/24 hours or g/10 mmol creatinine). Renal survival at 3, 5, and 10 years was 92%, 87%, and 64%, respectively.ConclusionPatients with presumed pFSGS often respond late to IS therapy. A decrease in proteinuria of >20% after 8 weeks of therapy is a predictor of responsiveness. Regardless of CR in some patients, improved biomarkers are needed to predict response/outcomes in patients with pFSGS.

Lupus Disease with Lupus Nephritis - 14 Years of Clinical-Biological Observations

Abstract We present the case of a female patient diagnosed in 2004 with systemic lupus erythematosus, initially with joint and hematological damage complaint, for which she was treated with Methylprednisolone for 6 months. Subsequently, symptomatology and paraclinical screening raised the suspicion of renal impairment, a pulse therapy with Solumedrol and Cyclophosphamide was initiated, a total of 6 pulses. She is in the database of our Clinic since March 2008, when a renal biopsy was performed, revealing a class IV lupus nephritis, initiating treatment with Mycophenolate mofetil and Prednisone until 2010, when the dose of Prednisone is progressively reduced until cessation at the time of remission. Subsequently she presented two relapse episodes, recovered by pulse therapy with Methylprednisolone and Cyclophosphamide, followed by maintenance therapy with Mycophenolate mofetil and Prednisone with a good clinical evolution. In 2017 the patient has a pregnancy with favorable evolution (under treatment with Azathioprine), presenting normal values of cDNA, C3, C4 during the 9 months, but with a persistent nephrotic-range proteinuria; in these conditions gives birth physiologically at 37 weeks. During 2019 apparent remission is maintained (stationary nitrogen retention, anti-dsDNA antibodies within normal range), but with moderate anaemia and persistent, but diminished proteinuria (being under treatment with reduced dose Prednisolone and Mycophenolate mofetil); along the way proteinuria is accentuated again and it is decided to return to reduced dose Azathioprine treatment, with good clinical evolution. Conclusion. The presented case reinforces the idea of systematic monitoring of patients with SLE and the need for permanent adaptation of treatment especially when there is an increased risk of relapse. Pregnancy, paradoxically well tolerated, increases subsequently the risk of reactivation of lupus nephritis.

Treatment response and progression to end stage renal disease in adolescents and young adults with lupus nephritis: A follow up study in an Egyptian cohort

BackgroundLupus nephritis (LN) badly affects the outcome in adolescents and young adults with systemic lupus erythematosus (SLE). Many have renal disease at onset and the significance of remission and relapse in adolescents and young adults is poorly evaluated. Aim of workTo outline the clinical and laboratory characteristics of treatment resistance, renal relapse and progression to end-stage renal disease (ESRD) in adolescents and young adults with LN. Patients and methodsEighty-five biopsy-proven LN patients were examined; SLE disease activity and renal damage were evaluated at baseline and followed up at 6 and 12 months. Laboratory and immunology profiles were assessed. Patients were evaluated for predictors of treatment response, renal flares, and renal survival. ResultsThe patients mean age was 15.12 ± 4.53 years. Female/male ratio was 10.5:1. 12.9% had treatment resistance, 87.1% achieved remission: complete (CR 31.8%) and partial (PR 55.2%) within 1st year. 27 (31.8%) developed a relapse within the 1st year (9 after CR and 18 after PR). Nephrotic range proteinuria persisted in 24 (28.2%) patients (13 PR and the 11 non-responders). Baseline hypertension (p = 0.034), persistent nephrotic range proteinuria (<0.001) and PR (p < 0.001) were predictive for renal flares. Treatment resistance (p = 0.021), disease relapse (p < 0.001), persistent nephrotic range proteinuria (p < 0.001) were predictors of ESRD, especially in males (p = 0.035). Autoimmune profile and histopathology class showed insignificant differences among groups. ConclusionPrevention and aggressive management of hypertension, proteinuria and renal flares is expected to prevent progression to ESRD in lupus nephritis in adolescent and young adult SLE patients.

Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy.

BackgroundImmunosuppressant drugs reduce proteinuria and anti-phospholipase A2 receptor autoantibodies (PLA2R-Ab) in primary membranous nephropathy (PMN) with varying success and associated toxicities. This study aimed to evaluate the effect of belimumab on proteinuria and PLA2R-Ab in participants with PMN.MethodsIn this prospective, open-label, experimental medicine study, 14 participants with PMN and persistent nephrotic-range proteinuria received up to 2 years belimumab monotherapy (10 mg/kg, every 4 weeks). Changes in proteinuria (urinary protein:creatinine ratio), PLA2R-Ab, albumin, cholesterol, B-cell subsets and pharmacokinetics were analysed during treatment and up to 6 months after treatment.ResultsEleven participants completed to the primary endpoint (Week 28) and nine participants completed the study. In the intention-to-treat population population, baseline proteinuria of 724 mg/mmol [95% confidence interval (CI) 579–906] decreased to 498 mg/mmol (95% CI 383–649) and 130 mg/mmol (95% CI 54–312) at Weeks 28 and 104, respectively, with changes statistically significant from Week 36 (n = 11, P = 0.047). PLA2R-Ab decreased from 174 RU/mL (95% CI 79–384) at baseline to 46 RU/mL (95% CI 16–132) and 4 RU/mL (95% CI 2–6) at Weeks 28 and 104, respectively, becoming statistically significant by Week 12 (n = 13, P = 0.02). Nine participants achieved partial (n = 8) or complete (n = 1) remission. Participants with abnormal albumin and/or cholesterol at baseline gained normal/near normal levels by the last follow-up. Adverse events were consistent with those expected in this population.ConclusionsBelimumab treatment in participants with PMN can reduce PLA2R-Ab and subsequently proteinuria, important preludes to remission induction.

Combination of tacrolimus and mycophenolate mofetil in persistent proteinuria due to refractory childhood lupus nephritis.

BackgroundChildren with lupus nephritis particularly, diffuse proliferative and membranous glomerulonephritis, may necessitate potent immunosuppressive medications and occasionally combined therapy.ObjectiveTo report the beneficial effects of tacrolimus (TAC) in children with refractory lupus nephritis from a single tertiary pediatric rheumatology clinic.MethodsThis is a retrospective case series of children with refractory lupus nephritis treated with TAC after failure of aggressive immunosuppressive treatment. All patients were evaluated at the time of initiation of TAC and at last follow-up visit by assessing the following response parameters: cSLE Disease Activity Index (SLEDAI), urine protein/creatinine ratio, urine sediments, serum albumin, complement (C3 and C4), anti-double-stranded DNA (dsDNA) antibody levels, and renal function assessed by glomerular filtration rate (eGFR).ResultsThree children (two girls and one boy) with lupus nephritis and persistent nephrotic-range proteinuria failed prednisone treatment as well as sequential treatment of cyclophosphamide, mycophenolate mofetil (MMF), and rituximab. When TAC was administered along with MMF and prednisone, all patients showed improvement in response parameters, namely, SLEDAI, serum albumin, and proteinuria, and prednisone doses were significantly weaned off and discontinued in two patients. However, eGFR remained stable during the treatment period. TAC was well tolerated, and no adverse effects were observed.ConclusionTAC combined with MMF can be considered as an alternative therapeutic option for children with refractory lupus nephritis particularly those with persistent nephrotic-range proteinuria.

Treatment Strategies of Adult Primary Focal Segmental Glomerulosclerosis: A Systematic Review Focusing on the Last Two Decades.

Adult primary focal segmental glomerulosclerosis (FSGS) remains a therapeutic challenge for the treating physician. With the advent of novel immunosuppressive measures, our arsenal of therapeutic options increased considerably. The aim of this review was to summarize reports published over the last two decades which reported on treatment outcome. Most reports included patients with a steroid-resistant (SR) disease course, yet the cohort with the highest unmet need, since persistent nephrotic range proteinuria is associated with a poor renal prognosis and portends a high risk of developing end-stage renal disease. While in first-line treatment, steroid treatment remains the recommended standard with an overall remission rate of 50% and higher, optimal treatment strategies for steroid-dependent/multirelapsing (SD/MR) and SR patients have to be defined. In both entities, calcineurin inhibitors showed good efficacy, while mycophenolate mofetil was less effective in SR cases compared to those with SD/MR. The same was true for rituximab, a monoclonal antibody targeting B-cells. In resistant cases, addition of extracorporeal treatment options or treatment with alkylating agents may be considered. To shape the future for treatment of FSGS, international collaborations to conduct larger clinical trials are needed to identify potential novel efficacious immunosuppressive or immunomodulatory therapies.

Re-treatment with high-dose prednisolone after rituximab infusion for childhood-onset steroid-resistant nephrotic syndrome

Sirs, We read with great interest the article titled “Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome” by Kamei et al., which has recently appeared in Pediatric Nephrology [1]. In this retrospective observational study of ten childrenwith refractory steroid-resistant nephrotic syndrome (SRNS), seven patients (70 %) achieved complete remission after receiving multiple courses of methylprednisolone pulse therapy (MPT) and immunosuppressive agents administered after one to four doses of rituximab (RTX). Although we agree with their speculation that a RTX infusion may improve the response to various immunosuppressants, such as steroids and cyclosporine A, little information is currently available on the optimal therapeutic protocol for children with refractory SRNS after administration of the biological agent. We previously described a 2-year-old girl with refractory SRNS resistant to nine courses of MPT (total 27 treatments) and cyclosporine A (6–7 mg/kg/day) following RTX infusion. Interestingly, the patient went into complete remission after re-treatment with conventional high-dose prednisolone (PSL, 2 mg/kg/day) administered after an additional RTX infusion within 2 weeks [2]. Recently, we encountered a SRNS patient resistant to multiple courses of MPTand mycophenolate mofetil who also achieved complete remission after re-treatment with high-dose PSL administered after an RTX infusion within a short period of time. This patient, an 8-year-old boy, presented with a 2-week history of significant weight gain and generalized edema. His medical history was significant for chronic kidney disease (estimated glomerular filtration rate 60–70 ml/min/1.73 m) as he had experienced septic shock associated with pneumococcal meningitis at the age of 1 year. On admission, a physical examination showed generalized edema, abdominal distention, and a blood pressure of 111/72 mmHg. His weight was 22.2 kg, which was increased by 2 kg compared to his dry weight. Laboratory investigations were as follows: white blood cell count, 72,000/mm; hemoglobin, 13.7 g/dl; hematocrit, 39.2 %; platelets, 221,000/mm; blood urea nitrogen, 23 mg/dl; serum creatinine, 0.61 mg/dl; sodium, 137 mmol/l; potassium, 4.4 mmol/l; chloride, 107 mmol/l; calcium, 7.7 mg/dl; phosphorous, 4.8 mg/dl; total protein, 3.9 g/dl; albumin, 1.6 g/dl; total cholesterol, 404 mg/dl; serum immunoglobulin G, 202 mg/dl, C3, 105 mg/dl, and C4, 18 mg/dl. Tests with antihepatitis B surface antigen, antihepatitis C antibody, and antinuclear antibody were negative. Urinalysis showed 1+ occult blood and 3+ protein by dipstick. The 24-h urine protein excretion was 4.9 g. Based on these findings, a presumptive diagnosis of idiopathic NS in the course of chronic renal insufficiency was made, and treatment with high-dose PSL (2 mg/kg/day) was initiated without a significant reduction in the amount of proteinuria. Persistent nephrotic-range proteinuria for more than 4 weeks with conventional steroid therapy prompted us to perform a renal biopsy with histology, which showed ischemic glomerular obsolescence. Since nephrotoxic drugs such as cyclosporine A were contraindicated based on the histological findings, the patient was treated with MPT (20 mg/kg/day for 3 consecutive days per week) for 3 weeks, followed by mycophenolate mofetil (30 mg/kg/day) and alternate-day low-dose PSL. However, proteinuria did not return to baseline values. After a single infusion of RTX (375 mg/m), a second course of high-dose PSL (2 mg/kg/ S. Fujinaga (*) Division of Nephrology, Saitama Children’s Medical Center, 2100 Magome, Iwatsuki-ku, Saitama City, Saitama 339 8551, Japan e-mail: f_shuich@d2.dion.ne.jp

A rare case of reversible acquired AA-type renal amyloidosis in a chronic filariasis patient receiving antifilarial therapy

Lymphatic filariasis is a major health problem in India with a large number of patients tending to be asymptomatic. In the Southeast and South Asian regions, Wuchereria bancrofti is the most prevalent parasite, causing filariasis in 99.4% of cases. While kidney involvement is a rare event in chronic filariasis, this case is unique because AA-type renal amyloidosis occurs in chronic W. bancrofti infection. We present here a unique case of lymphatic filariasis. The patient, a 25-year-old male who was previously diagnosed with right lower limb filarial lymphedema and had undergone lymphovenous anastomosis, was admitted for evaluation of persistent nephrotic-range proteinuria. Autoimmune markers in the form of anti-nuclear antibodies, anti-double-stranded DNA and anti-neutrophil cytoplasmic antibody were negative; C3 was normal. Urine analysis revealed inactive sediment with moderate proteinuria. Both serum and urine electrophoresis were negative for paraproteins and bone marrow aspirate and biopsy were normal. Evidence of active filarial infection was established on the basis of microfilariae in the peripheral smear and a positive W. bancrofti antigen test. Kidney biopsy revealed renal amyloidosis when stained with Congo red and anti-AA immunostain. The patient's proteinuria improved on conservative management with angiotensin-converting enzyme inhibitors and a course of antifilarial drugs. His proteinuria returned to <1g/24h with normalization of renal function and no significant proteinuria on periodic follow-up at 6-month and 1-year intervals. Repeat kidney biopsy after 1.5years showed regression of amyloidosis. Repeat demonstration of filarial antigen and microfilariae in the peripheral smear were negative on multiple occasions during the follow-up period. Although various chronic infections can lead to secondary renal amyloidosis, this is the first case reported in world literature where secondary amyloidosis developed as a complication of chronic filarial infection due to W. bancrofti. This is probably also the first case reported in world literature where renal amyloidosis has an etiological association with W. bancrofti infection and where patient symptoms improved with antifilarial and antiproteinuric management.

Idiopathic membranous nephropathy in children

Idiopathic membranous nephropathy (MN) is a rare cause of asymptomatic proteinuria (AP) or nephrotic syndrome (NS) in childhood. To improve our understanding of its clinical course, we retrospectively reviewed 19 cases of idiopathic MN seen in our hospital over a period of 28.5 years, i.e., from January 1977 to July 2005. Eight patients (39%) had AP and 11 (61%) presented with NS. All eight AP patients achieved remission, regardless of treatment modality. Oral corticosteroid was given to all 11 NS patients, but only three of them responded to corticosteroid. Of the eight steroid non-responders, three achieved remissions with the addition of cyclosporine, and the five who were not administered additional immunosuppressive drugs had persistent NS. At the latest evaluation, all six NS patients that achieved remission remained free of proteinuria and had a normal renal function. Moreover, two of the 5 steroid non-responders showed persistent nephrotic-range proteinuria but a stable renal function. The remaining three steroid non-responders progressed into chronic renal insufficiency, and this progression was preceded by renal vein thrombosis (RVT) in two of the three patients. Presentation with NS (P=0.045) and the development of RVT (P=0.010) were identified as poor prognostic factors.

Residual renal function: considerations on its importance and preservation in dialysis patients.

Residual renal function (RRF) remains important even after commencement of dialysis. Its role in the adequacy of peritoneal dialysis (PD) is well recognized and is increasingly utilized in incremental PD regimes, but it is also vitally important in hemodialysis (HD) patients, in whom it, as in PD patients, may improve survival. It may allow for a reduction in the duration of HD sessions. It reduces the need for dietary and fluid restrictions in both PD and HD patients. Other contributions include improved middle molecule clearance, better hemoglobin, phosphate, potassium, and urate levels, enhanced nutritional status and quality of life scores, and better outcomes in pregnancy. On the negative side, hypoalbuminemia may be prolonged in patients with persistent nephrotic-range proteinuria. Contrary to popular belief, RRF does not necessarily decline rapidly with the initiation of HD. PD may be better than HD in preserving RRF, although this difference may not persist if biocompatible membranes, bicarbonate buffer, and ultrapure water are used. Nocturnal ambulatory peritoneal dialysis (APD) patients may fare worse than continuous ambulatory peritoneal dialysis (CAPD) patients. RRF can be adversely affected by angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, and radiocontrast agents. Diuretics can help maintain fluid balance but not RRF.

ACE inhibition improves glomerular size selectivity in patients with idiopathic membranous nephropathy and persistent nephrotic syndrome

Patients with idiopathic membranous nephropathy (IMN) and persistent nephrotic-range proteinuria are at risk for progression to end-stage renal failure. Whether angiotensin-converting enzyme (ACE) inhibitors are also renoprotective in these patients remains elusive. In 14 patients with IMN (patients) and persistent proteinuria (protein > 3 g/24 h for >6 months), we studied mean arterial pressure (MAP), urinary protein excretion, glomerular filtration rate (GFR), renal plasma flow (RPF), and albumin and neutral dextran fractional clearance after 2 months washout from previous antihypertensive treatment (basal), after 2 months of enalapril (2.5 to 20 mg/d) therapy (posttreatment), and 2 months after enalapril withdrawal (recovery). MAP, proteinuria, and GFR were also measured at the same time points in 6 patients with IMN and persistent overt proteinuria maintained on conventional treatment throughout the study period (controls). Basal MAP, proteinuria, and GFR were similar in the two study groups. However, in patients at the end of the treatment period, MAP (posttreatment, 99.6 ± 11.2 versus basal, 103.3 ± 12.1 mm Hg; P < 0.05), proteinuria (posttreatment protein, 5.0 ± 2.9 versus basal, 7.1 ± 4.9 g/24 h; P < 0.05), albumin fractional clearance (posttreatment median, 1.7 × 10−3; range, 0.2 to 22.7 × 10−3 versus basal median, 4.1 × 10−3; range, 0.4 to 22.1 × 10−3; P < 0.05), and fractional clearance of largest neutral dextrans (radii from 62 to 66 Å) were significantly less than basal values. At recovery, MAP significantly increased to 106.6 ± 11.7 mm Hg (P < 0.001 versus enalapril), but all other parameters remained less than basal values. GFR and RPF were similar at each evaluation. Changes in proteinuria after treatment withdrawal positively correlated (r = 0.72; P < 0.01) with baseline GFR. Theoretical analysis of dextran-sieving data indicated that ACE inhibitor treatment significantly improved glomerular membrane size-selective dysfunction. This effect persisted more than 2 months after treatment withdrawal. No patient had symptomatic hypotension, acute renal function deterioration, or hyperkalemia during enalapril treatment. Thus, in patients with IMN and long-term nephrotic syndrome, ACE inhibitor treatment, but not conventional therapy, improves glomerular barrier size selectivity. The antiproteinuric effect of ACE inhibition is long lasting, especially in patients with more severe renal insufficiency. This is the premise of a long-term renoprotective effect that may limit the need for treatment with more toxic drugs.

Lupus Nephritis

Effective treatment of lupus nephritis requires an understanding of disease pathogenesis, risk stratification by World Health Organization (WHO) classification and therapeutic options. Mesangial lupus nephropathy is generally associated with an excellent prognosis, whereas proliferative lupus nephropathy, especially the diffuse variant, is often characterised by hypertension, red blood cell casts and significant deterioration of renal function. Nephrotic syndrome in the absence of hypertension, active urinary sediment or significant hypocomplementaemia suggests the membranous variant of lupus nephropathy. Membranous nephropathy generally confers a good prognosis. However, persistent nephrotic range proteinuria may be accompanied by loss of renal function and end stage renal disease. Glucocorticoids, usually prednisone or methylprednisolone, remain the most effective, rapidly acting immunomodulatory therapy for both the initial episode or recurrence of active renal disease. A role for cyclophosphamide in the treatment of lupus nephritis has been established in prospective, randomised trials. The benefits of intravenous cyclophosphamide were seen in groups of patients failing prednisone, establishing cyclophosphamide as salvage or rescue therapy for patients unresponsive to glucocorticoids. Additional therapeutic strategies include azathioprine, cyclosporin, and plasmapheresis. Ancillary management can consist of hypertension control, use of angiotensin-converting enzyme inhibitors, dietary restriction of salt and protein, and lipid lowering drugs. Current treatment of lupus nephritis is associated with preservation of renal function in the vast majority of patients; however, novel agents that are more effective and less toxic are required.

A controlled trial of cyclosporine in patients with progressive membranous nephropathy

A controlled trial of cyclosporine in patients diagnosed with progressive membranous nephropathy (MGN) was carried out to determine whether cyclosporine (D) would be more effective than placebo (P) in reducing the rate of deterioration in renal function. Patients (N = 64) with MGN were placed on a restricted protein diet (< or = 0.9 g/kg) and followed closely for 12 months (Part 1). Patients at high risk of progression based on an absolute loss in creatinine clearance (CCr) of > or = 8 ml/min and persistent nephrotic range proteinuria (Pr) were selected and randomly assigned to either (D) (N = 9) or (P) (N = 8) for 12 months (Part 2). No differences in the two groups were noted at entry. After 12 months, the improvement in CCr slope in ml/min/month was significantly greater in the D patients (D + 2.1 vs. P + 0.5, mean difference 1.6; 95% CI 0.3 to 3.0, P < 0.02). This improvement was maintained in six of eight D (75%) over a mean follow-up period of 21 months. Daily Pr also improved with D (by month 3, D - 4.5 g/day vs. P + 0.7 g/day, P = 0.02) and was sustained in six of eight (75%) D patients. When Pr was expressed as a function of their concurrent CCr, the D versus P patients' time to halving was faster (P = 0.02) and absolute number higher (4/9 D vs 0/8 P). In the D group a trend towards worse hypertension and an increase in the number of transient rises in serum creatinine were noted.(ABSTRACT TRUNCATED AT 250 WORDS)

New York University/Hospital for Joint Diseases experience with intravenous cyclophosphamide treatment: efficacy in steroid unresponsive lupus nephritis

The medical records of patients receiving cyclophosphamide for lupus nephritis between 1987 and 1993 at the New York University/Hospital for Joint Diseases Lupus Study Group Institutions were retrospectively reviewed. We identified 45 patients (38 female, seven male) who received a mean of 9 +/- 1 (range 2-23) pulses of intravenous cyclophosphamide for diffuse proliferative glomerulonephritis (n = 28), focal proliferative glomerulonephritis (n = 7), membranous nephropathy (n = 5), mesangial nephropathy with sclerosis (n = 1) or nephritis without biopsy (n = 4). Forty-two of the 45 patients received cyclophosphamide after failing steroid therapy. During a follow-up period of 52 +/- 3 months, nine patients progressed to end-stage renal disease (ESRD) with three additional patients experiencing a doubling of the creatinine and two patients persistent nephrotic range proteinuria. There were no deaths directly attributable to cyclophosphamide and no patients developed hemorrhagic cystitis or malignancy. Ten of 37 women had ceased menstruating prior to cyclophosphamide therapy. Treatment-associated amenorrhea occurred in only three patients all over 27 years of age. Intermittent intravenous cyclophosphamide therapy of lupus nephritis is well tolerated and usually effective in maintaining renal function in patients unresponsive to steroids although, in our experience, 20% of patients developed ESRD and a total of 14 of 45 (30%) patients had unsatisfactory outcomes.

Focal glomerulosclerosis in children: an Argentinian experience.

Twenty-six children presenting with idiopathic nephrotic syndrome and a histological diagnosis of focal glomerulosclerosis were studied retrospectively to evaluate their response to treatment, outcome and clinicopathological correlations. Twenty-two patients (84.6%) were steroid resistant; of these, 8 of the 19 with focal segmental glomerulosclerosis and 2 of the 3 with focal global glomerulosclerosis responded to cyclophosphamide (CY) within 16 weeks of starting therapy. Seven patients relapsed after a CY-induced remission, but 5 of them became steroid responsive. After an average follow-up of 83 months, 17 patients are in remission with normal renal function, 3 patients have persistent nephrotic range proteinuria and 6 patients are in chronic renal failure. Persistence of proteinuria, a high percentage of segmentally sclerotic glomeruli and diffuse mesangial proliferation were indicators of poor prognosis. We believe longer courses of CY therapy than those traditionally utilized are responsible for the relatively good results in our patients.