Tip variant of focal segmental glomerulosclerosis: is it truly a benign variant?

Abstract

Background: Even though frequently described as a benign entity, the outcomes of the tip variant of focal segmental glomerulosclerosis (FSGS) have proven to be unclear. Methods: This retrospective study includes a cohort of tip variant cases who presented to us from 2009 to 2012 and the analysis of their presenting clinical, histopathological features and treatment outcomes in comparison to the not otherwise specified (NOS) variants from our center in East India. Results: Of the 224 biopsies of primary FSGS, 30 cases were the tip variant (13.39%). The mean age of presentation was around 29 years, with 57% being males. A nephrotic presentation was seen in 87% of cases, with 20% showing a presentation at <18 years of age for the first time. Global sclerosis, interstitial fibrosis, tubular atrophy and arteriolar hyalinosis were seen more commonly in the NOS variant. Twenty five patients of tip variant received steroid therapy and eight received alternative immunosuppression. Around 87% of the tip variant cases achieved some form of remission in proteinuria and 13.3% had a doubling of creatinine at a median follow-up of 2 years in comparison to NOS group in which 80% achieved some form of remission and 20% had a doubling of creatinine. Conclusion: Though the histopathological features and treatment responsiveness of the tip variant appear to be better than the NOS variety, the prognostic outcome does not seem to be as favorable as implicated previously with an important percentage of patients showing progressive worsening of renal function within a relatively short time span (2 years) in our cohort.     

Cardiac disease in children with primary glomerular disorders—role of focal segmental glomerulosclerosis

Anecdotal reports suggest a higher frequency of serious cardiac complications, particularly cardiomyopathy and congestive heart failure (CHF), in children with focal segmental glomerulosclerosis (FSGS). We report the occurrence of cardiac disease in children with FSGS compared with other glomerular causes of primary nephrotic syndrome (NS). A chart review was performed on all patients evaluated at the Schneider Childrens Hospital between 1985 and 2003 with a diagnosis of membranoproliferative glomerulonephritis (MPGN), membranous nephropathy (MN), focal global glomerulosclerosis (FGGS), and FSGS. Clinical and demographic data were compiled, specifically whether or not the patient had clinically evident cardiac disease. The blood pressure (BP) and hematocrit in patients with FSGS and chronic renal failure (CRF) (glomerular filtration rate <30 ml/min per 1.73 m²) in the 3 months prior to the development of cardiac complications were compared with the values in FSGS patients with CRF but no cardiac complications, and in patients with the other causes of primary NS in whom CRF developed. There were 48 patients with FSGS, 22 with MPGN, 19 with MN, and 4 with FGGS. Cardiac disease occurred in 6 children (mean age 11 years), all with FSGS. Four of these patients were black and 5 were female. CHF occurred in all patients, cardiomyopathy in 4, and left ventricular hypertrophy in 5 patients. There was no significant difference in the BP and the hematocrit levels between the 6 patients with both FSGS and cardiac disease, 3 patients with FSGS and CRF but no cardiac disease, and the 5 patients with the other glomerulopathies in whom CRF occurred (P>0.1). Our findings suggest that there is a clinical association between FSGS and cardiac disease in pediatric patients. We speculate that the immune mechanism responsible for the development of FSGS may also affect the heart.     

Is focal segmental glomerulosclerosis increasing in patients with nephrotic syndrome?

Idiopathic nephrotic syndrome in children has conventionally been associated with minimal change disease. However, recent reports have conflictingly suggested that the frequency of focal segmental glomerulosclerosis (FSGS) in children might be on the increase, as has occurred in adults. The aim of the present work was to review the medical literature to ascertain whether an increase in the frequency of FSGS is occurring and, if so, to quantify such increase. We reviewed the studies comparing the frequency of FSGS in two consecutive periods over the past three decades (period 1 versus period 2). We pooled the data of the studies and then estimated FSGS frequency in two ways: (a) including in the denominator all patients with nephrotic syndrome and (b) including only patients who had undergone kidney biopsy. Both analyses were aimed to determine the odds ratio of FSGS occurrence in the second period. Six studies fulfilled the inclusion criteria, involving 1,149 patients with nephrotic syndrome. Four studies were used to calculate FSGS frequency, including in the denominator all nephrotic patients (n = 885), yielding an odds ratio of 2.22 (95% CI = 1.18–4.18). The analysis combining five studies with the number of biopsies in the denominator (n = 603) produced an odds ratio of 1.98 (95% CI = 1.12–3.50). These results suggest that a shift in the pathological pattern of nephrotic syndrome in children might be occurring, resulting in an increase in FSGS frequency. This hypothesis has major clinical significance due to the poorer prognosis associated with FSGS.     

How do mesangial and endothelial cells form the glomerular tuft?

The glomerular capillary tuft is a highly intricate and specialized microvascular bed that filters plasma water and solute to form urine. The mature glomerulus contains four cell types: Parietal epithelial cells that form Bowman's capsule, podocytes that cover the outermost layer of the glomerular filtration barrier, glycocalyx-coated fenestrated endothelial cells that are in direct contact with blood, and mesangial cells that sit between the capillary loops. Filtration begins only after the influx and organization of endothelial and mesangial cells in the developing glomerulus. Tightly coordinated movement and cross-talk between these cell types is required for the formation of a functional glomerular filtration barrier, and disruption of these processes has devastating consequences for early life. Current concepts of the role of mesangial and endothelial cells in formation of the capillary tuft are reviewed here.     

Is estimated donor glomerular filtration rate before death a better predictor of decreased-donor kidney function?

The worldwide shortage of deceased-donor kidneys for transplantation has become a serious issue in the past decade, leading to study of marginal donors. However, both the availability and the utility of kidneys from deceased donors are still unclear. The aim of the present study was to evaluate another method to estimate donor kidney function rather than using donor creatinine (Cr). We studied 129 recipients of deceased-donor kidneys from Maastriche donor categories III and IV. We analyzed donor Cr levels before death and recipient Cr levels at 1 year after transplant, as well as estimated glomerular filtration rates (eGFR). There was no significant difference in donor Cr levels at admission to the hospital and before death according to eGFR at 1 year after transplantation: <30 mL/min/1.73 m² versus ≧30 mL/min/1.73 m². However, recipients whose donors showed lower average eGFR levels on admission displayed better renal function at 1 year after transplant (P = .025). In conclusion, donor Cr levels before death was a less useful measurement to relate to recipient renal function; eGFR provided a better index.     

Is estimated peri-operative glomerular filtration rate associated with post-operative mortality in fractured neck of femur patients?

AIM: Comparison of renal function in patients who died within 30 days of surgery for hip fractures with surviving patients matched for age, type of surgery, type of anaesthesia and clinical assessment of fitness for surgery. MATERIALS & METHODS: A retrospective case-control study of 80 patients was performed. Pre- and post-operative urea, creatinine, estimated glomerular filtration rate (eGFR), sodium and potassium of 40 patients who died within 30 days post-surgery (cases) were compared with 40 patients who survived matched for age, sex, surgical procedure and pre-operative ASA grade (controls). Statistical analysis involved univariable analysis by paired t-test and logistic conditional regression analysis. RESULTS: Pre- and post-operative mean serum creatinine were significantly higher in patients who died compared with surviving controls (pre-op 108.2 vs. 90.2mumol/l [p=0.002], post-op 103.9 vs. 87.1mumol/l [p=0.003]). However, mean creatinine values for both groups were still within normal laboratory reference ranges. Mean serum urea was also higher in patients who died (pre-op 8.81 vs. 6.75mmol/l [p=0.010] and post-op 9.30 vs. 6.63mmol/l [p=0.004], respectively). Pre- and post-operative eGFR was significantly lower in those patients who died within 30 days of hip fracture surgery (pre-op 61.75 vs. 68.78ml/min per 1.73m(2) [p=0.011], post-op 63.03 vs. 76.03ml/min per 1.73m(2) [p=0.009]). The mean eGFR values for survivors and non-survivors fell in the chronic kidney disease mild renal impairment category. There were no significant differences in mean serum sodium or potassium concentration between groups. Stepwise conditional logistic regression analysis, showed that after allowing for creatinine, urea was no longer significantly related to mortality. CONCLUSION: These results suggest that when allowance is made for demography, fitness for surgery and surgical procedure, subtle reductions in eGFR are still associated with mortality risk. However, these are of questionable clinical use.     

The phenomenon of focal segmental glomerulosclerosis post-transplantation—a one-hit wonder?

Steroid-resistant nephrotic syndrome (SRNS), also termed focal segmental glomerulosclerosis (FSGS), is one of the most difficult conditions for the nephrologist to manage, particularly when the disease recurs post-transplantation. This syndrome is extremely interesting from the biological perspective as the non-genetic form is most likely caused by an as yet unknown disorder of the circulating plasma. This elusive ‘plasma factor’ has been the focus of researchers for several decades. Many hypotheses have been proposed and tested, but none have yet passed the test of clinical utility. However, the search appears to be narrowing, facilitated by landmark discoveries in the molecular properties of the glomerular filtration barrier, as well as by improved experimental tools. In the therapeutic/clinical setting, the targeting of specific molecules in treatments has improved, of which one example is treatment with specific monoclonal antibodies. In this context, our report on the effects of tumor necrosis factor-alpha (TNF-α) on podocytes is instructive as it demonstrates that this cytokine can have directly deleterious effects on podocytes in vivo and that this effect can be targeted clinically, potentially halting or reversing the disease process. As with all thought-provoking research, this result raises several interesting questions. Is TNF-α the elusive ‘plasma factor’ or is it one of several? Does it directly affect the glomerular filtration barrier, or does it modulate the immune response? And could this technique be used as a cell-based assay for disease activity? Our report adds another potential candidate to the growing list of candidates that need to be tested in a wider population of well-phenotyped patients with SRNS.     

Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?

BACKGROUND: We have described a group of patients who present with isolated chronic bronchodilator resistant non-productive cough with an atopic constitution, eosinophilic tracheobronchitis, and airway cough receptor hypersensitivity without bronchial hyperresponsiveness, which we have termed "atopic cough". Although cough variant asthma (in which the cough responds to bronchodilators) is recognised as a precursor of typical asthma, it is not known whether atopic cough is also a precursor of asthma. METHODS: Eighty two patients with atopic cough were retrospectively examined for onset of typical asthma and compared with 55 patients with cough variant asthma (20 untreated patients and 35 treated with long term inhaled beclomethasone dipropionate (BDP), 218-467 micro g/day). The median follow up period for patients with atopic cough and cough variant asthma was 4.8 (1-11.5) years and 3.7 (1-12.4) years, respectively. RESULTS: Onset of typical asthma occurred in only one of the patients with atopic cough. In patients with cough variant asthma, typical asthma developed in two of 35 patients taking BDP and six of 20 untreated patients (difference 24.3%, 95% CI 2.8 to 45.8, p<0.02). CONCLUSIONS: These findings suggest that cough variant asthma is a precursor of typical asthma but that atopic cough is not. Treatment with inhaled steroids may prevent the transformation of cough variant asthma into typical asthma.     

Is the simian virus SV40 associated with idiopathic focal segmental glomerulosclerosis in humans?

BACKGROUND: Glomerulosclerosis was reported in mice transgenic for the simian polyomavirus SV40 early region that contains the transforming sequences encoding the SV40 large T-antigen (TAG). This was discovered when an SV40 epidemic occurred following the use of contaminated polio vaccines during 1955-1963, and led to investigations that showed an association between SV40 infection and tumors in humans. We investigated the possible association of SV40 infection and idiopathic focal segmental glomerulosclerosis (FSGS). METHODS: The study was performed in 17 Bouin-fixed, paraffin-embedded renal biopsies from FSGS patients and 10 matched biopsies from patients with IgA glomerulonephritis; all patients had undergone polio vaccination in the early 1960s. Extracted DNA was polymerase chain reaction (PCR) amplified using SV.for3/SV.rev primers and GabE1/GabE2 primers; both sets of primers map in the region of SV40 TAG sequences, and amplify a fragment of respectively 105-bp and 135-bp. The biopsies considered were those in which the DNA was sufficiently intact to allow amplification of a fragment of 102-bp of the ApoE gene. RESULTS: Three FSGS and none of the IgA biopsies were positive for the SV.for3/SV.rev fragment. Conversely, amplification with GabE1/GabE2 primers did not lead to any specific product in either the IgA or FSGS biopsies. Restriction fragment length polymorphism and sequencing analyses revealed that the positive results obtained with the SV.for3/SV.rev primers were due to amplicons generated by multiple dimerization of forward and reverse primers. CONCLUSIONS: With the limited number of patients investigated, this study excludes the hypothesis that SV40 is associated with idiopathic FSGS.     

Is there a learning curve associated with the use of remifentanil?

This study prospectively determined whether there was a learning curve with the use of remifentanil, as indicated by decreased hemodynamic variability, improved recovery profile, and decreased incidence of opioid-related adverse events with increasing experience. Patients undergoing diverse surgical procedures (outpatient [n = 1340] and inpatient [n = 560]) were enrolled by investigators (n = 190) who had no previous experience with remifentanil use. Each investigator enrolled 10 patients. A standardized protocol for administration of remifentanil was used. Data were analyzed to determine differences between the first three patients and the last three patients enrolled for each anesthesiologist in the study. There were no differences in hemodynamic variables between the first triad and the last triad in either outpatients or inpatients. Requirements for hypnotic drugs and the doses of remifentanil used were also similar between groups. Analgesic medications administered at the end of surgery and in the postanesthesia care unit (PACU) were similar between groups, except that the last triad in the outpatient group received smaller doses of fentanyl compared with the first triad. Times to response to verbal command, tracheal extubation, and operating room discharge did not differ between groups. However, patients in the last triad undergoing outpatient surgery had shorter times to eligibility for PACU discharge, but times to eligibility for discharge home did not differ. The overall incidence of all adverse events (i.e., hypotension, hypertension, muscle rigidity, respiratory depression, apnea, nausea, and vomiting) was less in the last triad as compared with the first triad. When analyzed separately, only the incidence of vomiting (in the outpatient group) was decreased in the last triad as compared with the first triad. This study suggests that there is a learning curve that aids reduction of minor adverse effects associated with the use of analgesic medications administered at the end of surgery in outpatients, which might have reduced the incidence of postoperative vomiting and the duration of PACU stay. Implications: This study demonstrated that anesthesiologists rapidly acquire the ability to use remifentanil with limited experience. However, there is a learning curve that aids reduction of minor adverse effects associated with the use of analgesic medications administered at the end of surgery in outpatients, which might have reduced the incidence of postoperative vomiting and the duration of postanesthesia care unit stay.     

Lennert's lymphoma: a variant of cytotoxic T-cell lymphoma?

We studied 10 cases of Lennert's lymphoma (lymphoepithelioid lymphoma) to evaluate the cellular origin of the neoplastic cells. There were six men and four women, aged 38 to 75 years (median, 56 yrs; mean, 59 yrs). The lymphoma cells tended to remain confined to lymph nodes, and extranodal involvement was rare. The mean overall survival was 42.2 months, which is relatively good compared with other peripheral T-cell lymphomas. Morphologically, the lymph node was occupied by small to large clusters of epithelioid cells interspersed with medium to large atypical lymphoid cells. In seven cases, large atypical lymphoid cells resembling Hodgkin's or Reed-Sternberg cells were observed. The phenotypes of these neoplastic cells were CD3+ CD4- CD8+ in five cases, CD3+ CD4+ CD8- in four cases, and CD3+ CD4- CD8- in one case. TIA-1 was positive by immunohistochemical staining in seven cases, whereas four cases were positive for granzyme B. Clonal rearrangement of the T-cell receptor gene was confirmed in all cases by either Southern blot hybridization or a polymerase chain reaction-based denature gradient gel electrophoresis method. Epstein-Barr virus was negative by in situ hybridization in all but one case. Lennert's lymphoma was formerly known as a CD4+ helper T-cell neoplasm. Our results suggest that, at least in some cases, the neoplastic cells are of cytotoxic T-cell origin.     

Idiopathic granulomatous mastitis with erythema nodosum: Is it a variant of clinical presentation indicating treatment resistance? A retrospective cohort study

Idiopathic granulomatous mastitis (IGM) rarely occurs with erythema nodosum (EN) as a systemic finding. However, the impact of their coexistence on disease severity and response to steroids has not been investigated yet. Patients diagnosed with IGM between September 2014 and October 2018 were divided into two groups according to the presence or absence of EN during the first admission retrospectively. The IGM was more severe in patients with EN as it was presented more often as bilateral and diffuse involvement of the breast. Findings of mastitis did not resolve with steroids in 50% of this group. Repetitive excisions and mastectomy with reconstructions were required to control the disease. Coexistence of EN and IGM was found to be related to bilateral and aggressive involvement, which could be associated with insufficient response to steroids. Associated patients should be informed in terms of the aggressive course, and surgery can be highlighted as a first‐line treatment.     

Acute fall in glomerular filtration rate with renin-angiotensin system inhibition: a biomeasure of therapeutic success?

Glomerular filtration rate (GFR) acutely declines with the introduction of renin-angiotensin system inhibition. This response is functional, not anatomical, and varies with volume status. The reduction in GFR with renin-angiotensin system inhibition may serve as a biomeasure of future therapeutic benefit.     

Impact of PCI-neo-HGF on the expression of TGF-β1 and proliferation of glomerular mesangial cells in rats

肾小球系膜细胞(GMC)的过度增生是导致肾小球硬化及肾间质纤维化的重要机制之一[1].肝细胞生长因子(HGF)是一种多效性的细胞因子,其可通过加速细胞外基质降解,阻断小管上皮细胞转分化等实现对肾脏的保护[2-4].目前HGF对正常及增生的GMC是否有抑制作用尚不明确.本研究采用可在体内持续平稳表达的PCI-neo-HGF质粒进行研究[5],主要探讨HGF是否能抑制正常及脂多糖(LPS)刺激后的大鼠GMC的增生,以及这种作用是否与抑制转化生长因子β1(TGF-β1)的表达相关.     

Is central sarcopenia a predictor of prognosis for patients with pathological fracture?

IntroductionWe aimed to investigate the relationship between central sarcopenia and survival in patients with pathological fracture.MethodsWe reviewed records of patients who were treated for pathological fracture of axial and appendicular skeleton in our clinic between 2011 and 2020. We used the psoas: lumbar vertebral index (PLVI) on axial computer tomographic evaluation to assess for central sarcopenia. A multivariate Cox algorithm was applied to recognize these factors independently associated with one month, six months, one year, and overall survival.ResultsA total of 147 patients [61 (41.4%) male and 86 (58.6%) female] were included, with an average age of 62.4 years. During the study, 108 (73.4%) patients died, and 39 (26.6%) were alive. The survival rates at 1 month, 6 months, and 1 year after surgery were 94.6%, 68.7%, and 53.1%, respectively. PLVI values ranged from 0.21 to 1.20 with a mean of 0.536 and a median of 0.520. According to the median value of PLVI, 68 patients with sarcopenia had low PLVI and 79 patients without sarcopenia had high PLVI. For the first month, only the preoperative albumin level was identified as a prognostic factor. Eastern Cooperative Oncology Group Performance Status (ECOG), American Society of Anesthesia (ASA) scores and primary malignancy (rapid grade) were strong predictor of poor survival. The PLVI was independent significant predictor of first month (HR, 0.083 [95% CI, 0.011–0.649], p = 0.018) and overall survival (HR, 0.129 [95% CI, 0.034–0.492], p = 0.003).ConclusionThe PLVI was a strong predictor of first year, and overall survival in patients with pathological fracture.