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Background: Steroid-resistant nephrotic syndrome (SRNS) is a major cause of stage 5 chronic kidney disease (CKD 5) in children. LDL apheresis (LDL-A) is now FDA approved for the treatment of pediatric focal segmental glomerulosclerosis (FSGS). Effective management of hyperlipidemia with LDL-A in SRNS patients may prevent progression of kidney disease and lead to remission. We report a case series of patients who received LDL-A for treatment of SRNS METHODS: We describe five children with SRNS who were treated with 12 sessions of LDL-A. Partial remission (PR) is defined as urine protein to creatinine ratio (UPC) of 0.2-2 (g/g) or decrease in UPC ≥ 50%, and complete remission (CR) is defined as UPC < 0.2 (g/g)., Results: One patient achieved CR and three achieved PR. One patient did not respond to therapy. The earliest that a patient achieved PR was at treatment #10 and some did not respond until after LDL-A was completed. Those who responded stayed in either CR or PR for extended periods of time. LDL-A was successful at significantly reducing LDL (p < 0.001), total cholesterol (p < 0.001), and triglyceride (p < 0.001)., Conclusions: LDL-A was able to significantly decrease the lipid levels in these patients and induce CR and PR in the majority. The current study confirms previous studies showing those with a higher glomerular sclerosis burden were less likely to respond. LDL-A should be considered in patients with treatment-resistant SRNS and should be considered before there is a high burden of glomerular sclerosis to provide the best chance of success., (© 2021. IPNA.)

Background: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. To date, few studies have investigated predictive factors for treatment responses in recurrent FSGS., Methods: We retrospectively analyzed 16 patients who were < 16 years at the age of onset and had post-transplant recurrence of FSGS from 1993 to 2018. Patients who achieved complete remission or partial remission after initiating therapy for recurrent FSGS were defined as responders. We compared several clinical characteristics between responders and non-responders. Time to remission was also analyzed., Results: Ten patients were responders, and six patients were non-responders. Univariate analysis showed that responders had a significantly lower amount of maximum proteinuria at the time of recurrence (P = 0.015) and more highly selective proteinuria (P = 0.013) than non-responders. The time to remission from initiation of therapy was 2 months (interquartile range 0.2-4.4). In all responders, except for one patient, remission was achieved within 6 months., Conclusions: Therapeutic responses may be predicted by examining the amount and selectivity of proteinuria at the time of recurrence. Further studies with larger numbers of patients are clearly required to validate these findings.

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) is associated with a slower progression to end-stage renal disease (ESRD) in pre-dialysis patients. However, little is known about the associated mortality risks after transitioning to dialysis., Methods: This retrospective cohort study included 0-21 year-old incident dialysis patients from the United States Renal Data System starting dialysis between 1995 and 2016. We examined the association of CAKUT vs. non-CAKUT with all-cause mortality, using Cox regression adjusted for case mix variables. We also examined the mortality risk associated with 14 non-CAKUT vs. CAKUT ESRD etiologies and under stratification by estimated glomerular filtration rate (eGFR)., Results: Among 25,761 patients, the median (interquartile range) age was 17 (11-19) years, and 4780 (19%) had CAKUT. CAKUT was associated with lower mortality, with an adjusted hazard ratio (aHR) of 0.72 (95%CI, 0.64-0.81) (reference: non-CAKUT). In age-stratified analyses, CAKUT vs. non-CAKUT aHRs (95%CI) were 0.66 (0.54-0.80), 0.56 (0.39-0.80), 0.66 (0.50-0.86), and 0.97 (0.80-1.18) among patients < 6, 6-< 13, 13-< 18, and ≥ 18 years at dialysis initiation, respectively. Among non-CAKUT ESRD etiologies, the risk of mortality associated with primary glomerulonephritis (aHR, 0.93; 95%CI 0.80-1.09) and focal segmental glomerulosclerosis (aHR, 0.89; 95%CI, 0.75-1.04) were comparable or slightly lower compared to CAKUT, whereas most other primary causes were associated with higher mortality risk. While the CAKUT group had lower mortality risk compared to the non-CAKUT group patients with eGFR ≥5 mL/min/1.73m 2 , CAKUT was associated with higher mortality in patients with eGFR < 5 mL/min/1.73 m 2 ., Conclusions: CAKUT is associated with lower mortality among children < 18 years old, but showed comparable mortality with non-CAKUT among patients ≥ 18 years old. ESRD etiology should be considered in risk assessment for children initiating dialysis.

Background: Focal segmental glomerulosclerosis (FSGS) in pediatric patients is typically difficult to treat and will progress to end-stage renal disease (ESRD) in about 10% of cases. Following kidney transplantation, FSGS can recur in up to 56% of renal allografts-with a near 100% recurrence in subsequent transplants., Methods: Four different pediatric centers across the USA and the UK employed a protocol using LDL-apheresis (LDL-A) and pulse solumedrol to treat recurrent FSGS after transplantation in seven patients. All the patients included in this series demonstrated immediate, or early, recurrence of FSGS, which clinically presented as nephrotic-range proteinuria within hours to days after implantation of the kidney., Results: All patients experienced reductions in urinary protein to creatinine ratios resulting in partial or complete remission. All patients demonstrated improvements in their estimated GFRs at their most recent follow-up since LDL-A discontinuation., Conclusions: This case series describes the successful treatment, across four different pediatric centers, of seven pediatric patients with recurrent post-transplant FSGS using the Liposorber® LA-15 in combination with pulse solumedrol.

Low-density lipoprotein (LDL) apheresis has been used increasingly in clinical practice for the treatment of renal diseases with nephrotic syndrome (NS), specifically focal segmental glomerulosclerosis (FSGS). Persistent hyperlipidemia for prolonged periods is nephrotoxic and leads to chronic progressive glomerular and tubulointerstitial injury. Effective management of hyperlipidemia with HMG-CoA reductase inhibitors or LDL apheresis in drug-resistant NS patients may prevent the progression of renal disease and, in some patients, resolution of NS symptoms. Available literature reveals beneficial effects of LDL apheresis for NS refractory to drug therapy. Here we update on the current understanding of lipid nephrotoxicity and application of LDL apheresis to prevent progression of renal diseases.

Background: Low birthweight infants have a reduced number of nephrons and are at high risk of chronic kidney disease. Preterm birth and/or intrauterine growth restriction (IUGR) may also affect peritubular capillary development, as has been shown in other organs., Case-Diagnosis/treatment: We report two patients with a history of preterm birth and extremely low birthweight who showed polycythemia and renal capillary rarefaction. Patient 1 and 2, born at 25 weeks of gestation with a birthweight of 728 and 466 g, showed mild proteinuria at age 8 and 6 years, respectively. In addition to increasing proteinuria, hemoglobin levels became elevated towards adolescence and their serum erythropoietin (EPO) was high despite polycythemia. Light microscopic examination of renal biopsy specimens showed glomerular hypertrophy, focal segmental glomerulosclerosis, and only mild tubulointerstitial fibrosis. A decrease in the immunohistochemical staining of CD31 and CD34 endothelial cells in renal biopsy specimens was consistent with peritubular capillary rarefaction., Conclusions: Since kidney function was almost normal and fibrosis was not severe, we consider that the capillary rarefaction and polycythemia associated with elevated EPO levels were largely attributable to preterm birth and/or IUGR.

Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in children and adolescents and nearly 50 % of affected patients will progress to end-stage kidney disease over a 5 to 10-year period. Unfortunately, there is no established treatment for disease in the native kidney. Moreover, up to 55 % of patients develop recurrent disease after receiving a kidney transplant, with a substantially higher risk in patients who have already experienced recurrent disease in a prior transplant. A number of clinical and laboratory factors have been identified as risk factors for this complication. In addition, new investigations into podocyte biology and circulating permeability factors have shed light on the cause of recurrent the disease. While a number of novel therapeutic agents have been applied in the management of this problem, there still is no proven treatment. In this review, we summarize recent advances in the epidemiology, pathophysiology, and treatment of recurrent FSGS in pediatric patients who have received a kidney transplant.

Background: The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid-resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity., Case-Diagnosis/treatment: A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS., Conclusions: This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene.

Background: Focal segmental glomerulosclerosis (FSGS) recurs in 20-40 % of allografts. Plasmapheresis (TPE) has been one of the mainstays of treatment with variable results. Rituximab (RTX), a monoclonal antibody to the protein CD20, is being used for treatment of recurrent FSGS (recFSGS) but pediatric experience is limited., Methods: We conducted a retrospective review of eight patients with recFSGS, treated with RTX (1-4 doses) after having minimal response to TPE. Complete response was defined as a decrease in urine protein creatinine ratio (Up/c) to less than 0.2 and partial response was a decrease in Up/c ratio by 50 % of baseline and in the sub-nephrotic range (U p/c <2)., Results: Complete response was seen in two of eight patients, and partial response was seen in four of eight patients. Two patients had no response. At last follow-up, all the partial responders had sub-nephrotic range proteinuria (Up/c ratios ranging from 0.29 to 1.6). Delayed response, up to 9 months post-RTX, was also seen in some of the patients. Significant complications such as rituximab-associated lung injury (RALI), acute tubular necrosis, and central nervous system(CNS) malignancy were also observed in our case series., Conclusions: Rituximab can be used with caution as a treatment for recFSGS. Efficacy is variable from none to complete response. Even partial reduction in proteinuria is of benefit in prolonging the life of the allograft. Long-term, multicenter studies are needed to prove its sustained efficacy in those who respond and to monitor for serious adverse effects.

Background: In the absence of mutant genes encoding components of the podocyte slit diaphragm, about 30-50 % of children with primary glucocorticoid-resistant focal segmental glomerulosclerosis (FSGS) develop recurrent proteinuria and slowly progressive FSGS lesions following renal transplantation. Recurrence of FSGS in the allograft strongly suggests a circulating factor that disturbs normal podocyte biology. To date, the nature of the circulating factor is unclear, and there is no cure for the recurrent form of FSGS (R-FSGS)., Methods: Cultured differentiated human podocytes were exposed to the plasmapheresis effluent or blood plasma samples from pediatric patients with recurrent or primary FSGS; in some cases, podocytes were pre-incubated with specific antibodies to block the tumor necrosis factor-alpha (TNFα) signaling pathway. Integrity of focal adhesion complexes and actin cytoskeleton were investigated by immunofluorescent microscopy., Results: Plasmapheresis effluent from an R-FSGS child or fresh plasma from two children with primary FSGS rapidly disturbed the cytoskeleton of normal human podocytes in vitro. Plasma from a child with R-FSGS also activated β3 integrin and dispersed focal adhesion complexes. The effects were reversed by pre-incubation with antibodies against TNFα or either of the two TNFα receptors. When our patient with R-FSGS became resistant to plasmapheresis, we initiated treatment with twice weekly etanercept injections and then infliximab. Within 3 weeks of regular anti-TNFα therapy, the patient achieved sustained partial remission of proteinuria, allowing us to wean her off plasmapheresis completely., Conclusions: We suggest that in some FSGS patients, disruption of the podocyte cytoskeleton and β3 integrin-mediated podocyte attachment are driven by the TNFα pathway.

Focal and segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome in adults and children. It is responsible for 5-20% of all cases of end-stage kidney disease (ESKD) in the United States. The pathogenesis of FSGS has not been fully elucidated; however, data from molecular studies of familial cases in the last two decades suggest that FSGS is a defect of the podocyte. The therapeutic agents available for treatment of FSGS are not very effective and only a small percentage of affected individuals will achieve complete remission. Recent data from molecular biology and molecular genetics has provided insight into the mechanisms of action of old agents and also identification of other novel therapeutic targets. This review focuses on recent advances in the molecular pathogenesis of FSGS and currently available therapeutic agents as well as potential novel therapies.

Corticosteroid-resistant nephrotic syndrome (CRNS) with focal and segmental glomerulosclerosis (FSGS) is a heterogeneous disorder and the most severe and frequent type of all glomerulopathies in children leading to end-stage renal failure. The podocyte is at the center of development and progress of FSGS; this unique cell type plays a major role in the integrity of glomerular structure and permeability. The rate of complete remission of CRNS after induction therapy using different immunosuppressant agents is reported to range between 30% and 84%, depending on the treatment schedule and on the underlying defects of FSGS. Children with genetic types of FSGS barely respond to immunosuppressant therapies and over-treatment prior to transplantation should be avoided. The response of children with an idiopathic type of FSGS to immunosuppressants is superior to those with genetic FSGS. However, many children with idiopathic FSGS do not enter complete remission if they are under-treated, for example, with short-term immunosuppressant monotherapies. If immunosuppressant treatment fails, these patients will have to undergo renal transplantation. However, as unknown pathogenetic mechanisms may persist, more than one-third of these patients with idiopathic FSGS develop a rapid recurrence of CRNS that responds poorly to further long-term therapeutic attempts. In contrast with previously published data, this review takes into account recently identified genetic etiologies of CRNS, and superior results with long-term combination therapy in idiopathic forms to avoid over- and under-treatment.

We report on a 12-year-old female patient with steroid-dependent nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) since her 3rd year of life. She was twice treated with oral cyclophosphamide and received antihypertensive treatment with atenolol and enalapril. After 3 years without any control or therapy, she presented in a reduced general condition with hypertensive crisis and a blood pressure of 220/130 mmHg, headache, vomiting and loss of vision. Additionally, renal insufficiency (creatinine 11.4 mg/dl, urea 157 mg/dl), with oliguria, anaemia and a severe relapse of nephrotic syndrome, was present. Initial treatment with steroids, albumin-furosemide infusions and antihypertensive drugs was unsuccessful, and dialysis treatment was necessary. Renal biopsy showed an advanced stage of the known FSGS and, surprisingly, a thrombotic microangiopathy. Further diagnostic investigations revealed no signs of haemolytic-uraemic syndrome, but echocardiography showed left ventricular hypertrophy, and hypertensive retinopathy grade 3 was diagnosed, making severe hypertension the most likely reason for the thrombotic microangiopathy. While adequate antihypertensive treatment led to regress of left ventricular hypertrophy and hypertensive retinopathy, renal function did not recover, and the patient remained dialysis-dependent. In conclusion, severe hypertension in chronic kidney disease can lead to target organ damage and thrombotic microangiopathy, which may further worsen renal function.

There have been few reports on successful treatment for focal segmental glomerulosclerosis (FSGS) complicated by leukoencephalopathy. We report the efficacy of the steroid pulse and mizoribine (MZB) combined with plasmapheresis (PP) for a case of FSGS with leukoencephalopathy induced by cyclosporine (CyA). The patient was a 4-year-old boy with FSGS who presented with steroid-resistant nephrotic syndrome (NS) and was treated with CyA. On the 7th day after starting CyA, he complained of one visual disorder, and hypertension and tonic convulsions were observed. Electroencephalography (EEG) revealed generalized slow waves, and magnetic resonance imaging (MRI) disclosed high signal intensity in the white matter. A diagnosis of leukoencephalopathy induced by CyA was made on the basis of these findings with the improvement in clinical manifestations upon discontinuation of CyA. We treated the patient with steroid pulse therapy and MZB combined with PP, and the proteinuria gradually decreased and only microscopic hematuria remained. We report that steroid pulse and MZB combined with PP may be an effective treatment in a patient with FSGS complicated by CyA-induced leukoencephalopathy.

Recently, there have been reports on the efficacy of low-density lipoprotein (LDL) apheresis (LDL-A) for focal and segmental glomerulosclerosis (FSGS) in pediatric patients. However, there have been few reports on the long-term efficacy of LDL-A for FSGS in such patients. We report here a case of long-term efficacy of LDL-A for FSGS. The patient was a 13-year-old boy with FSGS who presented with steroid-resistant and cyclosporine-resistant nephrotic syndrome and hyperlipidemia. LDL-A was performed 24 times on one year. Following LDL-A, serum concentrations of LDL, very low-density lipoprotein (VLDL), apoprotein B, and vascular endothelial growth factor significantly decreased, and urinary excretion of protein also decreased. In addition, 3 years after LDL-A, the pathology findings on a second renal biopsy had improved. The patient has been in remission from FSGS for 12 years since LDL-A. These findings suggest that LDL-A may be useful in maintaining long-term remission from pediatric FSGS.

Focal segmental glomerulosclerosis (FSGS) is known to recur in approximately 30% of renal allografts with graft loss in about half of these cases. The exact etiology remains unclear, though a putative circulating permeability factor or loss of inhibitory substances is being discussed. Different therapeutic approaches have been used. We report on a 10-year-old Arabian boy with a recurrence of FSGS immediately after transplantation. In addition to intensifying immunosuppressive therapy with high-dose cyclosporin A and cyclophosphamide, plasmapheresis was initiated and remission was achieved after 8 months. Three weeks after cessation of plasmapheresis a relapse occurred. Plasmapheresis was resumed and remission was achieved again after four additional sessions. The interval between plasmapheresis treatments was then gradually increased and fourteen months after transplantation plasmapheresis was stopped again. Since then (1.5 years after cessation of treatment) the patient has been in complete remission without any further episode of proteinuria. In conclusion, complete and sustained remission with stable renal function was achieved in our patient by long-term plasmapheresis in combination with intensified immunosuppression. Therefore, continuation of plasmapheresis treatment should be considered even in the situation of initial non-response.

Recurrence of focal glomerulosclerosis (FSGS) following renal transplantation is a common cause of allograft loss and clinical morbidity. Recent attempts to control proteinuria and morbidity with plasmapheresis (PP) have met with limited success. Our experience with the use of mycophenolate mofetil (MMF) and angiotensin blockade (AB) in the management of refractory FSGS pre transplant suggested its potential benefit in post-transplant recurrence. This report presents our 25-year experience in pediatric renal transplantation of patients with FSGS divided into two treatment eras: Era 1-prior to use of daclizumab (anti-IL-2R) and Era 2-after daclizumab. A total of 179 pediatric patients were transplanted during the 25-year period. FSGS was confirmed in 27 (15%); 16 of 28 allografts (57%) had recurrence of FSGS during the post-transplant period. In Era 1, only 6 of 16 (38%) recurred in the allograft, while 10 of 12 (83%) recurred during Era 2. The odds ratio of recurrence of FSGS in the allograft after induction with anti-IL-2R was 8.3 (95% confidence interval=1.3-52, P =0.02). Only 2 patients in Era 1 received PP, while 10 in Era 2 were entered into an intensive PP protocol followed by maintenance with AB consisting of angiotensin receptor blockers alone, or in combination with angiotensin-converting enzyme inhibitor. Although proteinuria decreased an average of 80+/-16% with PP, the response was variable and severe morbid edema persisted in poor responders. Maximum benefit occurred with the addition of AB and MMF. After a follow-up of 27+/-15 months, proteinuria has shown a sustained decrease of 94+/-8% below baseline. In conclusion, our experience suggests that, with recurrent FSGS, a limited course of PP followed by maintenance therapy with AB and MMF improves symptoms and may preserve allograft function.

From January 1985 to July 2000, a retrospective study of 53 patients in Taiwan was performed in order to evaluate the underlying diseases causing heavy proteinuria and the clinical outcome in children under 2 years of age (33 boys and 20 girls). Renal biopsy or autopsy was performed in 26 of the children. Renal pathology revealed 2 patients with congenital nephrosis (CNS) (7.7%), 4 with diffuse mesangial sclerosis (DMS) (15.4%), 4 with minimal change nephrotic syndrome (MCNS) (15.4%), 5 with focal segmental glomerulosclerosis (FSGS) (19.2%), 9 with IgM nephropathy in (34.6%), and 2 with hepatitis B virus-associated membranous glomerulonephritis (7.7%). Based on available histology and family history of heavy proteinuria progressing to end-stage renal disease (ESRD), patients were divided into two groups. Group I comprised 10 patients, including CNS (2 cases), DMS (4 cases), and 4 children with a familial history of heavy proteinuria progressing to ESRD. All patients in group I were initially steroid resistant. After methylprednisolone pulse therapy plus cyclosporin A treatment, no patients with CNS or DMS responded, but the other 4 patients experienced a remission. Group II comprised 43 patients; 19 patients (44.2%) were initially steroid resistant. Of these steroid-resistant patients, all experienced remission after methylprednisolone pulse therapy plus cyclosporin A, except 3 children with FSGS. One experienced a thromboembolic event during his clinical course. In conclusion, steroid-resistant nephrotic syndrome (NS) was more common than steroid-sensitive NS in Chinese patients under 2 years of age. Patients with CNS, DMS, or a family history of heavy proteinuria progressing to ESRD had a poor prognosis. Methylprednisolone pulse therapy plus cyclosporin A treatment achieved remission in some children who were initially steroid resistant. This study indicates that children with conditions associated with poor steroid responsiveness (e.g., CNS, DMS) do not respond to immunosuppressive therapy, but other children under 2 years of age, including those with a family history of progression to ESRD, may benefit from aggressive immunosuppressive therapy.

Recurrence of focal segmental glomerulosclerosis (FSGS) in an allograft is a challenging clinical situation because it frequently results in graft loss. We report our experience with early use of plasmapheresis in recurrent FSGS. Of the 18 (33%) children with biopsy-proven FSGS (in their native kidneys) transplanted at our institution, 6 had recurrence (elevated urine protein/creatinine ratios) post transplant and were treated with plasmapheresis. Patients who received treatment within 1 day of the recurrence (4/6) went into remission after 5-13 plasmapheresis treatments, within 5-27 days of starting treatment. Patients who did not respond to plasmapheresis (2/6) were treated 7 and 17 days after onset of proteinuria; 1 of these had acute tubular necrosis and acute rejection leading to graft loss and the other developed acute rejections, ongoing proteinuria, and subsequent graft loss. All 4 patients who went into remission have maintained good graft function, 22-53 months post transplant. In our experience early institution of plasmapheresis for recurrent post-transplant proteinuria in FSGS is effective.

Transient or intermittent plasmapheresis with concurrent immunosuppressive therapy is thought to be beneficial in the treatment of recurrent focal segmental glomerulosclerosis (FSGS) in the early post-transplant period. The results of long-term (6-year) plasmapheresis therapy, in a 9-year-old female with an immediate recurrence of FSGS [urinary protein/urinary creatinine (UP/UC)=17.7] after cadaveric renal transplant, are presented. A 4-week plasmapheresis course induced a decline in the proteinuria, but a relapse occurred after cessation of plasmapheresis. Addition of protein A column therapy led to a further decrease in the proteinuria, to a non-nephrotic range. Long-term control of the nephrotic syndrome was established using a chronic treatment regimen consisting of a single-volume plasmapheresis, followed by a protein A column treatment, performed on sequential days every 3-4 weeks. Mean UP/UC values decreased to 1.15+/-0.9. A course of cyclophosphamide was successfully used to control a worsening of proteinuria 4 years post transplant. Although sequential renal biopsies demonstrated progressive glomerular sclerosis, the patient's mean calculated creatinine clearance only modestly declined from 78.3 ml/min per 1.73 m2, at the time of transplantation, to 62.7 ml/min per 1.73 m2, 6 years later. This patient demonstrated dependence on plasmapheresis/protein A column therapy to maintain a clinical remission of her FSGS recurrence. While long-term plasmapheresis and protein A column therapy in combination with immunosuppressive therapy reversed the effects of uncontrolled nephrosis and possibly facilitated long-term renal allograft survival, the glomerular sclerosis continued to progress.

We report an 8-year-old Caucasian boy who presented with steroid-resistant nephrotic syndrome. Renal biopsy showed the cellular variant of focal segmental glomerulosclerosis (FSGS). Within 1 year he received a series of therapies that have induced remission in other patients with this disease, all to no avail (conventional-dose cyclosporin A, methylprednisolone pulse therapy, high-dose cyclosporin A, and therapy with mycophenolate mofetil). He achieved remission after five sessions of plasma exchange. This case argues for aggressive therapy of resistant nephrotic syndrome in the native kidney. Plasma exchange should be considered as a possible rescue therapy arm in future study protocols.

In primary focal and segmental glomerulosclerosis (FSGS) renal prognosis is poor if no remission of proteinuria can be achieved with treatment. Currently, most children with FSGS are treated with cyclosporine and steroids after establishing steroid resistance, and approximately 60% of patients benefit from this therapy. For the remaining 40%, no generally approved therapeutic recommendations exist for children. We treated nine children with cyclosporine-resistant primary FSGS with plasma exchange (PE), two with relapsing FSGS after renal transplantation and seven with FSGS in their native kidneys. Three patients did not respond to PE, but five came into complete remission and one patient achieved partial remission. Three patients relapsed between 6 weeks and 2 years following cessation of PE, and were subsequently treated with plasma immunadsorption (PIA), which also reliably reduced proteinuria. The patients without response to PE tended to have a longer duration of the disease. We conclude that PE and PIA are a useful option for treatment of steroid- and cyclosporine-resistant FSGS, particularly if applied early in the course of the disease. Although more demanding on supportive resources, PIA seems preferable to PE, since there is no necessity for additional albumin or fresh-frozen plasma, as with PE.

We report on three children with severe, recurrent focal segmental glomeruloscerosis (FSGS) in their first allografts, treated with methylprednisolone, plasma exchange and cyclophosphamide. This protocol is based on a previous publication showing its successful use in three children. Our patients were 2 girls and 1 boy, aged 14.5, 14.6 and 13.2 years, respectively, at transplant. Concomitant immunosuppression included cyclosporin A and prednisolone. Recurrence occurred in all three patients within 24 h, and specific treatment was commenced within 48 h. All patients developed anuria and were dialysed. The boy stopped dialysis after 4 weeks, and has stable chronic renal failure (CRF) and no proteinuria 3 years later. One girl required dialysis for 4 months, and 3 years later has CRF with non-nephrotic range proteinuria. The other girl remained dialysis-dependent and died from septic complications. We conclude that even anuric patients treated with this protocol may have an improvement in renal function and reduction of proteinuria, which can last for over 3 years. However, treatment may need to be prolonged and carries the substantial risks of heavy immunosuppression.

Individuals with focal segmental glomerulosclerosis (FSGS) are at risk for recurrence of disease following renal transplantation. The rate of recurrence has been estimated to range from 20% to 30%. The factors associated with an increased probability of recurrence are not known, although the rapidity of progression of disease, age at onset, and the presence of diffuse mesangial proliferation in the native kidney have all been implicated. We analyzed the data from 35 patients with FSGS who received 37 renal transplants at this institution between October 1968 and December 1997. Recurrence was diagnosed by the development of nephrotic-range proteinuria and a transplant biopsy compatible with the diagnosis. Sixteen recurrences were noted, with an overall recurrence rate of 43%. The risk of recurrence was associated with the use of antilymphocytic serum (ALS) for initial induction therapy; being 11% in those who received no induction therapy versus 53% in those who received ALS. Furthermore, in the latter group, the rate of recurrence was 88% in those who received antithymocyte globulin (ATGAM) versus 40% in those who received Minnesota antilymphocytic globulin. Factors such as race, sex, age at time of diagnosis, rapidity of progression to end-stage renal disease (ESRD), response to alkylating agents and/or cyclosporin therapy prior to ESRD, age at time of transplant, donor source, and triple or double immunosuppressive therapy did not appear to have an effect on the rate of recurrence. We conclude that induction therapy with ALS at time of transplantation increases the risk of recurrence of FSGS following renal transplantation.

We describe three adolescent patients on chronic hemodialysis with a pubertal growth spurt who developed severe hyperparathyroidism during recombinant human growth hormone treatment. Parathyroid hormone levels were raised in parallel with the increase in linear growth in all patients. In two patients, hyperparathyroidism was successfully controlled with an increase in calcitriol dosage. In the third patient, growth hormone had to be withdrawn. We discuss the possibility that puberty is a risk factor for the development of hyperparathyroidism during growth hormone therapy.

In patients with proteinuria, African-American (AA) ethnicity is reported to be a risk factor for focal segmental glomerulosclereosis (FSGS) and its progression to end-stage renal disease (ESRD). We reviewed our single-center experience to determine the probability of FSGS and its progression to ESRD based on ethnicity and age at presentation in children with proteinuria with or without nephrotic syndrome. Proteinuria without systemic disease or acute glomerulonephritis was the presenting feature in 17% (236/1,403) of children in the renal patient database of Texas Children's Hospital, Baylor College of Medicine. Histopathological diagnoses were established in 107 of 236 patients (45%). FSGS was identified in 65 patients, accounting for 28% of all patients with proteinuria and 61% of patients who underwent renal biopsy. FSGS was more prevalent in AA (45%) than in non-AA patients (22%) (P=0.001), and AA patients with FSGS were older at presentation (12.7+/-4.4 years) than non-AA patients (5.6+/-4.6 years) (P<0.001). Among patients who underwent renal biopsy, increasing age at presentation increased the probability of having FSGS in AA but not non-AA patients (P=0.04). Five-year actuarial renal survival of FSGS was worse in AA (8%) than in non-AA patients (31%) (P=0.01). These data suggest an increased risk and worse outcome of FSGS in AA compared with non-AA children.

We review our 20-year experience of 636 children with nephrotic syndrome (NS) in Durban, South Africa; 306 (48.2%) were blacks, 307 (48.2%) Indians and 23 (3.6%) were a mixed group (coloured); 91 (14.3%) could not be categorised and were excluded from the analysis. In Indian children, 134 of 286 (46.8%) had biopsy-proven minimal change NS (MCNS) and 94.8% of these were steroid sensitive (SS); 60 (21%) had SSNS but without renal biopsy; 59 (20.6%) had focal segmental glomerulosclerosis (FSGS), with only 4.4% of these being SS. In blacks, membranous nephropathy accounted for 40% of cases; 86.2% were associated with hepatitis B virus antigens. Typical SSNS continues to be uncommon among blacks. Only 14.4% had either biopsy-proven SS-MCNS or SSNS; 32 had MCNS lesions on biopsy, but 18 were steroid resistant (SR); 67 of 236 (28.4%) had FSGS, all of whom were SR. Among coloured patients, 5 of 23 (21.7%) had biopsy-proven SS-MCNS and or unbiopsied SSNS; 10 (43.5%) had FSGS and 6 of 23 (26.1%) had membranous nephropathy. Proliferative lesions were present in only 2 of 23 (8.6%) coloured patients and was uncommon in all population groups. Overall mortality was 3.1%. In brief, this is the largest reported series of NS among children in Africa and shows a typical pattern in Indians, an unusual pattern of histological types in blacks and an intermediate picture in coloureds.

Over the last 2 decades, we have learnt that focal segmental glomerulosclerosis (FSGS) is a ubiquitous phenomenon underlying the progressive deterioration of many different types of renal diseases in both pediatric and adult populations. FSGS may also be the primary renal lesion, whether in new disease entities such as glycogen storage disease and human immunodeficiency virus infection, or in idiopathic FSGS. Although the mechanism which triggers the development of primary FSGS still remains unknown, laboratory and clinical studies have identified several key pathophysiological events leading to end-stage renal disease. While therapeutic modalities have not changed remarkably, a recent study, although uncontrolled, demonstrated an impressive efficacy of intravenous steroid pulse therapy in inducing remission. Nevertheless, it remains largely unknown whether such a forced remission decreases the overall risk of developing chronic renal failure. Studies have revealed an important pathophysiological role of angiotensin and the therapeutic efficacy of angiotensin converting enzyme inhibitors in progressive loss of renal function in diseases where glomerulosclerosis is secondary; however, it remains to be verified whether these results hold true in primary FSGS. As a result of the improvement in allograft survival rate, the benefit of renal transplant outweighs the risk of recurrence of FSGS, hence transplantation continues to be a vital therapy for FSGS patients who have reached renal failure. Thus, FSGS is not one disease, but rather a range of lesions seen in many settings. The type of lesions and the patient's unique genetic factors contribute to prognosis, and also may dictate choice of optimum therapy.

The success rates of living-related donor (LRD) transplants are clearly superior to those obtained with cadaver donors. However, caution should be exercised when considering LRD transplantation for a condition which has an increased chance of recurring after transplantation and causing ultimate graft failure. The recurrence rate of focal segmental glomerulosclerosis (FSGS) in the allograft is 20%-40%, with graft failure resulting in 40%-50% of these cases. However, these figures may be an underestimation of the true rate of recurrence of FSGS. Once a first transplant fails due to recurrent disease, the risk of recurrence in the second transplant approaches 80%. Subgroups of patients at high risk for recurrence have been identified. In patients not at high risk for recurrent FSGS, the use of a LRD should be considered, provided that the donor and recipient and their families have been informed that the disease may recur and lead to graft failure. In patients at high risk for recurrence, a LRD transplant should be avoided. Hopefully, future development of a simple and reliable test to predict the likelihood of recurrence will enable us to counsel and advise our patients with FSGS about the wisdom or dangers of proceeding with a LRD transplant.

Varying components of the syndrome of human immunodeficiency virus nephropathy (HIVN) have been described, the most pertinent including proteinuria/nephrotic syndrome, progressive azotemia, normal blood pressure, enlarged and hyperechoic kidneys, rapid progression to end-stage renal disease (ESRD), and no response to treatment regimens. The diagnosis of HIVN requires identification of excessive proteinuria or albuminuria, determined by a total protein excretion on a timed urine collection or a high protein/creatinine ratio in a random specimen. Various pathological lesions have been found in HIVN. The lesion of focal and segmental sclerosis (FS/FSS) is most characteristic in adults and usually is associated with a rapid demise. FS/FSS also has been described in approximately one-half of the pediatric patients reported in the literature (31/64). Despite progression to ESRD, the clinical course in children with HIVN is less fulminant than in adults. Other reported histological findings include primarily mesangial hyperplasia as well as minimal change, focal necrotizing glomerulonephritis or lupus nephritis, and hemolytic uremic syndrome. In addition to glomerular pathology, interstitial findings of dilated tubules filled with a unique proteinaceous material, atrophied tubular epithelium, and interstitial cell infiltration are very common. On electron microscopy, most investigators have found tubuloreticular inclusion bodies in endothelial cells of glomerular capillaries. Treatment of patients who develop ESRD remains highly controversial. Most adult patients treated with hemodialysis have succumbed rapidly; peritoneal dialysis has been better tolerated. Transplantation in patients with HIV infection must be considered to be tentative, with reports of acceleration towards full blown acquired immunodeficiency syndrome in some and uneventful 5-year survival in others.(ABSTRACT TRUNCATED AT 250 WORDS)