Focal Global Sclerosis Research Articles

Dent disease: A window into calcium and phosphate transport.

This review examines calcium and phosphate transport in the kidney through the lens of the rare X‐linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC‐5, a Cl−/H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC‐5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC‐5 KO models suggests that ClC‐5 mediates parathormone endocytosis from tubular fluid. In addition, ClC‐5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.

The Histomorphological Spectrum of Renal Lesions in an Autopsy Study

Background: Autopsy provides normal as well as diseased human tissue for morphologic studies, for establishment of cell and organ culture as well for xenotransplantation. It provides the opportunity to discover new diseases, to evaluate toxic effects of drugs and therapies. The kidneys are often affected by chronic inflammatory lesions, neoplasms , toxic effects of various drugs and metabolic disorders. Methods : This was a five year study from January 2011 to December 2015 in our department of pathology. The kidneys of medico legal autopsies performed during these years were subjected to our study. After excluding 30 cases of severely damaged tissue, 120 cases of well preserved renal medico legal autopsies were included in our study. The stained microscopic sections were examined by two histopathologists independently. Results: Seventy five of the 120 autopsies were males, while 45 were females. In 27 (22.5%) cases, the microscopic morphology was close to normal histology. Remaining 93(77.5%) cases had a nephropathological findings The percentage of non glomerular nephropathies (60.8%) was higher as compared to that of glomerular lesions (16%). 20 (16% ) cases exhibited glomerular alterations such focal global glomerular sclerosis, segmental glomerular sclerosis, nodular mesangial sclerosis, basement thickening and mesangial cellular proliferation. Tubular and interestium lesions were observed in 34.16% which included acute tubular necrosis, chronic pyelonephritis and tubercular pyelonephritis. Renal arteriosclerosis was observed in 25% cases. Renal cell carcinoma was incidentally detected in1.6% Conclusion :Our study provided satisfactory data in respect to morphological spectrum of various renal lesions in autopsy. DOI: 10.21276/APALM.1455

The pathological spectrum associated with the ultrastructural finding of thin glomerular basement membrane: A tertiary medical city experience and review of the literature

ABSTRACTBackground: Thin glomerular basement membrane (GBM) has been noted in several glomerular diseases including IgA nephropathy, focal segmental glomerulosclerosis (FSGS), Fabry’s disease, and Alport’s syndrome. We conducted this study to investigate the pathological ultrastructural spectrum of thin GBMs, to identify associated diseases, and to measure the GBM thickness in thin GBMs in our adult population. Materials and methods: All renal biopsies with thin GBM, diagnosed between 2010 and 2016, were retrieved and reviewed. Results: Of 24 cases, 50.0% were diagnosed with FSGS, 12.5% with IgA nephropathy, 8.3% with tubulointerstitial nephritis, 4.2% with acute thrombotic microangiopathy, 4.2% with focal global sclerosis, 4.2% with lupus nephritis, and 16.7% with only thin GBM disease. Mean GBM thickness was 213.4 ± 24.7 nm. Mean interstitial fibrosis/tubular atrophy percentage (IF/TA) was 27.9 ± 22.2%. There was no significant correlation between GBM thickness and patients’ age or IF/TA percentage. Conclusion: The association of thin GBM with FSGS and IgA nephropathy is high. Morphometric analysis of the GBM thickness should be made routine, noting that ethnic variations in the GBM thickness are reported. Cases of thin GBM should be reported to facilitate proper diagnosis and institute the most appropriate treatment.

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid.

Long-term nephrotoxicity of ifosfamide is occasionally progressive, and, in such case, there has been no specific treatment to prevent progression. It has been reported that the presence of karyomegalic interstitial nephritis, which is rare type of interstitial nephritis, may be related to ifosfamide-induced nephropathy with poor prognosis and resistant to the immunosuppressive therapy. A 15-year-old boy presented with progressive nephrotoxicity 3years after systemic chemotherapy with ifosfamide and cisplatin for the treatment of osteosarcoma. Renal biopsy revealed the severe tubulointerstitial nephritis with tubular atrophy and focal global and segmental glomerular sclerosis. It also showed tubular epithelial cells with variably sized nuclei, some of which were massively enlarged, abnormal hyperchromatic, irregular shaped, and bizarre-appearing. These morphological changes were suggestive of the histology of karyomegalic interstitial nephritis. Corticosteroid retarded the progression of nephrotoxicity. The present case is the first report, suggesting that corticosteroid was effective against the late-onset renal toxicity by ifosfamide therapy. Our case also suggests that karyomegalic interstitial nephritis may be the result of long-term nephrotoxicity of ifosfamide. Since concurrent treatment with cisplatin is one of the risk factors for ifosfamide nephrotoxicity, there is a possibility that cisplatin may have a synergetic effect with ifosfamide for producing karyomegalic interstitial nephritis.

Ahmedabad tolerance induction protocol and chronic renal allograft dysfunction: pathologic observations and clinical implications

BackgroundChronic Renal Allograft Dysfunction (CRAD) is responsible for a large number of graft failures. We have abrogated acute T-cell rejections using Ahmedabad Tolerance Induction Protocol (ATIP) with hematopoietic stem cell transplantation (HSCT) under non-myeloablative conditioning pre-transplant. However B-cell mediated rejections and CRAD continue to haunt us. We carried out retrospective analysis of renal allograft biopsies performed in the last 4 years to evaluate the effect of ATIP on CRAD.Materials and methodsBiopsies diagnosed as per modified Banff criteria belonged to 2 groups: ATIP under low dose immunosuppression of cyclosporine/Azathioprine/Mycofenolate mofetil+ Prednisolone, subjected to donor leucocyte transfusion, anti-T/B cell antibodies, low dose target specific irradiation, cyclophosphamide, cyclosporin followed by HSCT pre-transplant; controls who opted out of ATIP were transplanted under standard triple drug immunosuppression. Demographics of both groups were comparable.ResultsIncidence of chronic changes was higher in controls (17.5%) vs. 10.98% in ATIP over a mean follow up of 151.9 months in the former and 130.9 months in the latter. Proteinuria and hypertension were higher in controls (48.4%) vs. ATIP (32.7%) with chronic transplant glomerulopathy, focal global sclerosis in 67.7% in controls vs. 46.7% in ATIP, acute on chronic T/B cell rejection in 51.6% controls vs. 28.1% ATIP, with peritubular capillary C4d deposits in 19.4% controls vs. 1.9% ATIP biopsies. Acute on chronic calcineurin inhibitor toxicity was higher in ATIP (71.9%) vs. 48.4% in controls.ConclusionChronic immune injury was less with ATIP vs controls as compared to a higher incidence of chronic calcineurin inhibitor toxicity in the former.

Dominant T cells in idiopathic nephrotic syndrome of childhood

Because of several studies, idiopathic nephrotic syndrome (INS) of childhood is suspected to have an immunologic pathogenesis with T cells playing a major role. To investigate this hypothesis further, we studied the diversity of the CDR3 region of the T-cell receptor (TCR) beta-chain from peripheral T cells isolated from patients with INS. The study was performed over a three-year period to obtain longitudinal data on the repertoire of peripheral T cells. mRNA from peripheral mononuclear cells (PBMCs) of seven INS patients and two healthy controls (NHD) was prepared and analyzed for CDR3 length polymorphism of TCR beta-chain by spectratyping. All INS patients presented individually skewed spectratype histograms in at least one Vbeta-family. Patients suffering from a frequent relapsing course of INS or a focal global sclerosis showed some alterations to persist in all samples isolated in the observation period (up to 3 years). In addition, sequence analyses of the beta-chain of the TCR CDR3 region confirmed clonal expansion of peripheral T cells in those patients who had displayed spectratype alterations. The data give strong evidence for an direct involvement of CD8+ T cells in the complicated course of INS.

Thin glomerular basement membrane disease: light microscopic and electron microscopic studies.

Benign recurrent hematuria usually indicates a good prognosis. This condition is associated with abnormally thin glomerular basement membranes. Of 680 renal biopsy cases in which lower urinary tract disease had been excluded by careful study, 25 cases from seven children and eighteen adults met the criteria for thin glomerular basement membrane disease, placing the incidence of the disease at 3.7%. The mean patient age was 32.4 years and the male to female ratio was 1 to 5.3. The primary finding was microscopic hematuria in eighteen patients and gross hematuria in five patients. Among eighteen patients who had microscopic hematuria, one patient also exhibited proteinuria and one patient suffered from acute renal failure due to acute drug-induced interstitial nephritis. Proteinuria was only found in one patient. All of the patients had normal renal function, with the exception of one who suffered from acute renal failure. The duration of hematuria from the time of detection to the date of biopsy ranged from 3 months to 30 years with a mean interval of 56.6 months. No apparent evidence of familial hematuria in any patient was noted. Under light microscopy most glomeruli were normal. However, five cases showed focal global sclerosis. Under immunofluorescence microscopy seventeen cases were negative for all immunoglobulins, for complement, and for fibrinogen. Eight cases showed nonspecific mesangial deposition of fibrinogen and/or IgM. Ultrastructurally, extensive diffuse thinning of the GBM was a constant finding. The mean thickness of the GBM was 203.2 +/- 28.3 nm (n = 25); the thickness in adult (201.4 +/- 27.5 nm; n = 18) did not differ from that in children (208.1 +/- 32.0 nm; n = 7).

Cyclosporin A in refractory idiopathic nephrotic syndrome: 5 years clinical experience

The use of cyclosporin A (Cy A) in idiopathic nephrotic syndrome, particularly lesions of focal segmental glomerular sclerosis, is controversial. A retrospective study of 10 adult patients with nephrotic syndrome treated with Cy A was performed. Histological diagnosis was established in all patients: focal segmental glomerular sclerosis (n = 6), focal global sclerosis (n = 1), mesangial proliferative glomerulonephritis (n = 1), focal proliferative glomerulonephritis (n = 1) and minimal change disease (n = 1). All patients had previously received immunosuppressive therapy (duration of steroids 1-76 months; 35.0 +/- 12.1, mean +/- SEM). Cy A in a dose of 3-5 mg/kg/day, reduced proteinuria from 16.85 +/- 6.67 to 3.37 +/- 1.48 g/24 hours (P = 0.008), with an associated increase in serum albumin from 15.2 +/- 2.6 to 34.3 +/- 2.5 g/l (P < 0.001). In six patients steroid therapy was discontinued. Cy A was well tolerated for up to 5 years. There was no significant nephrotoxicity. In conclusion, Cy A was effective treatment of refractory idiopathic nephrotic syndrome, including those cases with focal segmental glomerular sclerosis.

Focal sclerosing glomerulopathy risk factors of progression and optimal mode of treatment

Focal sclerosing glomerulopathy and especially focal segmental glomerulosclerosis (FSGS) have been recognized as a distinct clinical entity, however, there still exist controversies in terms of prognostic risk factors of progression and optimal mode of treatment. A total of 32 patients (2 with focal global sclerosis; FGS, the remainder with FSGS) were followed up for a mean period of 82 months (3-240 months). Fourteen presented with nephrotic syndrome and 18 had proteinuria with or without hypertension. Thirteen patients, all of whom except 1 were nephrotic, received steroid treatment with or without other immunosuppressive agents (cyclophosphamide/cyclosporin A/azathioprine). Three of the steroid-treated remained stable in complete remission; 5 nephrotic non-responders had renal death. The mean slope of 1/creatinine versus time for steroid-treated and non-treated groups was -0.23 and -0.043, respectively (p = 0.04), suggesting that nephrotic range proteinuria might be prognostically important. However, for the population of FSGS/FGS as a whole, only the initial serum creatinine predicted renal survival (p = 0.001 by Cox's regression model). Hypertension and hypercholesterolaemia were not important variables by themselves. Nevertheless, we found that the 9 patients treated with antihyperlipidaemics (gemfibrozil/probucol/cholestyramine/maxEPA) fared better, mean slope being -0.023 versus -0.103 for non-treated, though not reaching statistical significance (p = 0.96). Controlled prospective study involving a larger number of patients might be worthwhile.

Response to Cyclophosphamide Therapy in Saudi Children with Idiopathic Nephrotic Syndrome

Thirty-three children with idiopathic nephrotic syndrome received an eight-week course of 2.5 to 3.0 mg/kg of body weight of cyclophosphamide. Twenty-five (76%) were in remission 12 to 28 months la...

Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: superiority of response to corticosteroid therapy over histopathologic patterns.

To determine the utility of steroid response in classifying childhood nephrotic syndrome, we reviewed 119 biopsies in 92 children aged 1 to 16 years who had been followed for a mean of 7.2 years. Steroid responses were classified as steroid resistant, steroid dependent, and frequent relapser as defined by the International Study of Kidney Disease in Children. Biopsy specimens were classified as showing focal glomerulosclerosis (FSGS) in 39 children, as showing lipoid nephrosis in 28, and as questionable in another 25 with either focal global sclerosis, IgM nephropathy, or mesangial prominence and tubular changes. A strong agreement (p less than 0.01) was found between children whose FSGS was steroid resistant and children whose lipoid nephrosis resulted in frequent relapses. The length of the remission after therapy with chlorambucil or cyclophosphamide was determined in 84 children. A significantly shorter length of remission after cytotoxic drug therapy (p less than 0.05) was identified for patients with FSGS versus those with lipoid nephrosis; this difference became more significant for steroid-resistant patients in comparison with those who were steroid dependent or were frequent relapsers (p less than 0.005). Among all steroid-resistant patients, those with FSGS had shorter remissions than patients with other histologic changes (p less than 0.001). The data suggest that patterns of response to corticosteroid therapy correlate with the histologic abnormality. Thus steroid-sensitive patients need not undergo renal biopsy before receiving cytotoxic drugs. Steroid-resistant patients would benefit from a biopsy, because the findings tend to predict the outcome.

Persistent renal damage following pre‐eclampsia: A renal biopsy study of 13 patients

Renal biopsy material was examined from 13 patients who had a history of pre-eclampsia and who were biopsied after delivery. The characteristic 'endotheliosis' associated with pre-eclampsia appeared to resolve at varying rates and was not seen in biopsies taken more than 1 month after delivery. Four of the biopsies showed residual focal segmental glomerular lesions which are described. Focal global glomerular sclerosis (eight biopsies), focal interstitial scarring (seven biopsies) and arteriolo-sclerosis (nine biopsies) were also identified. These findings support those earlier reports which indicated that pre-eclampsia is capable of producing persistent renal damage in a small but significant percentage of cases.

No evidence for a specific role of IgM in mesangial proliferation of idiopathic nephrotic syndrome

AbstractNo evidence for a specific role of IgM in mesangial proliferation of idiopathic nephrotic syndrome. To define the relationship of mesangial IgM to various morphologic categories of idiopathic nephrotic syndrome (INS), an analysis of 100 patients was carried out in which five morphologic subgroups were evaluated: group 1, minimal glomerular change (38 patients); group 2, minimal change with focal global sclerosis (18 patients); group 3, focal segmental glomerulosclerosis (FSG) (23 patients); group 4, mesangial proliferation (12 patients); group 5, focal segmental glomerulosclerosis with mesangial proliferation (9 patients). Immunohistochemical studies failed to demonstrate any differences between these five groups. The intensities of immunofluorescence and the percentage of tissue samples demonstrating IgM and/or C3 in the glomerular mesangium and subendothelial regions were similar. In addition, the presence or intensity of mesangial IgM did not predict the patients' current status or responsiveness to steroid therapy. Morphologic transitions were observed in patients who had more than one biopsy: one of five in group 2 and two of eight in group 3 developed mesangial proliferation; and nine often patients with mesangial proliferation in the first biopsy continued to show this finding in the second. In general, a complete response to steroid therapy and a favorable outcome is less likely in patients with this morphologic abnormality. In nine of the 27 repeat biopsies, there was lack of agreement between the first and second tissue samples with respect to the presence or absence of mesangial IgM. Although mesangial proliferation is a consistent feature of the morphology of certain patients with INS, these studies do not support a unique association with mesangial IgM.Absence de preuve d'un rôle spécifique de l'IgM sur la prolifération mésangiale du syndrome néphrotique idiopathique. Afin de définir la relation entre IgM mésangiale et les différentes catégories morphologiques de syndrome néphrotique idiopathique (INS), une analyse de 100 malades a été effectuée, avec évaluation de cinq sous-groupes morphologiques: groupe 1, lésions glomérulaires minimes (38 malades); groupe 2, lésions minimes avec sclérose globale focale (18 malades); groupe 3, glomérulosclérose focale et segmentaire (FSG) (23 malades); groupe 4, prolifération mésangiale (12 malades); groupe 5, glomérulosclérose focale et segmentaire avec prolifération mésangiale (9 malades). Les études immunohistochimiques n'ont pas permis de démontrer de différences entre ces cinq groupes: Les intensités en immunofluorescence et le pourcentage des exemples tissus indiquant de l'IgM et/ou du C3 dans le mésangium glomérulaire et les régions sous endothéliales étaient identiques. De plus, la présence ou l'intensité de l'IgM mésangiale ne préjugeait pas de l'état des malades, ni de la réponse au traitement stéroïdien. Des transitions morphologiques ont été observées chez des malades qui avaient plus d'l biopsie: un sur cinq dans le groupe 2 et deux sur huit dans le groupe 3 ont développé une prolifération mésangiale; neuf de dix malades avec une prolifération mésangiale à la première biopsie ont continué à avoir cette anomalie à la seconde. En général, une réponse complète au traitement stéroïdien, et une évolution favorable sont moins probables chez les malades ayant cette anomalie morphologique. Dans neuf des 27 biopsies répétées, il y avait un manque de concordance entre la première et la seconde en ce qui concerne la présence ou l'absence d'IgM mésangiale. Bien que la prolifération mésangiale soit une caractéristique morphologique habituelle chez certains malades avec INS, ces études ne sont pas en faveur d'une association unique avec l'IgM mésangiale.

IgM associated primary diffuse mesangial proliferative glomerulonephritis.

Twenty-three cases of IgM associated primary diffuse mesangial proliferative glomerulonephritis are presented. In 18, IgM was the sole localising host immunoglobulin, and it was the predominant globulin in five; C3 was also present in 18. Light microscopy revealed variable diffuse and global mesangial proliferation in all cases, with additional focal global sclerosis in 16, focal segmental sclerosis in 15, and small capsular crescents in seven. Material for electron microscopy was available from 19 patients; in 13, occasional intramesangial electron dense deposits were identified, and in 18 there were irregular, rather ill defined areas of increased electron density in mesangial regions. Clinically, 14 patients presented with the nephrotic syndrome, and nine had asymptomatic proteinuria. During follow-up, only 10 patients showed no change in renal function or improved; the remainder showed increasing hypertension and/or renal function deterioration and four developed end stage renal failure. It is suggested that IgM associated mesangial proliferative glomerulonephritis should be considered as a distinct clinicoimmunopathological entity.

Familial Hyperuricemia and Renal Disease

Information on a familial syndrome of hyperuricemia and renal disease with or without gout was obtained on 33 of 41 blood relatives: Nine had renal disease; abnormalities of the urinary sediments were minimal; serum uric acid levels were elevated in seven and were not measured in two. Hyperuricemia was noted in three additional family members without evidence of renal disease. Goulty arthritis (three patients) did not precede renal disease. One individual had hyperuricosuria. The following erythrocyte purine enzyme levels were normal: adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, phosphoribosylpyrophosphate, synthetase, adenosine deaminiase, and purine nucleoside phosphorylase. Renal biopsy specimens showed focal global and segmental sclerosis of glomeruli, occasional hypercellularity, foci of atrophic tubules, chronic interstitial inflammation, and folding and wrinkling of glomerular basement membrane without electron-dense deposits. There were no immunofluorescent abnormalities.

IgA localisation in glomerular diseases.

The structural changes found on light and electron microscopy study of 25 renal biopsy specimens that showed significant glomerular IgA deposition on immunofluorescence were correlated with relevant clinical data. The morphology of a wide range of glomerulopathies seeen included mesangial proliferative (60%), membranous (12%), rapidly progressive proliferative (8%), mesangio-capillary (8%), and no light microscope change (8%). Four of the 15 cases (60%) of mesangial proliferative glomerulonephritis were associated with focal segmental sclerosis and 10 with focal segmental and focal global sclerosis. In addition, 7 of the 15 cases showed capsular crescents. The clinicopathological correlations indicated that the prognosis in this group is unfavourable when focal global sclerosis and capsular crescents are present, particularly when both occur in the same biopsy specimen.

The significance of focal sclerotic lesions of glomeruli in children

To establish the relationship between the type of focal sclerotic lesion of glomeruli and the development of progressive renal disease, the clinical courses of 20 children with focal segmental and 7 with focal global sclerosis were analyzed. Only five patients, all of them with focal segmental sclerosis, did not have the nephrotic syndrome, although all had proteinuria. Results suggest that patients with focal global sclerosis have a course identical to that of children with the minimal lesion form of nephrotic syndrome: onset in early childhood, response to steroid therapy, and a relapsing, nonprogressive course. Focal segmental sclerosis, in constrast, is characterized by older age at onset, high incidence of nephritic symptoms, lack of response to steroid therapy, and a progressive course with histologic and functional deterioration. Since most published reports have not distinguished between these two entities, a more favorable prognosis in focal segmental sclerosis may be inferred than is actually the case.

PROGNOSIS OF GLOMERULAR FOCAL SCLEROSIS IN CHILDREN

It is generally stated that focal sclerotic lesions of the glomeruli are associated with a poor prognosis. Nodistinction is usually mode between focal global sclerosis (complete hyalinization of affected glomeruli) and focal segmental sclerosis (hyalinization of only one area of the affected glomeruli). Seventeen children with focal sclerosis were surveyed to determine whether the type of lesion has prognostic significance. Four children, 3 male 1 female, presenting with nephrotic syndrome (NS) at the age of 13 to 19 months, were found to have focal global sclerosis. They all responded to prednisone therapy, relapsed frequently, and have normal renal function 9 to 14 years later. The 13 children with focal segmental sclerosis ranged in age from 1½ to 13 years; 7 were male and 6 female. Eleven presented with NS. Of these, 2 have died, 2 have received renal transplants, and 5 have mild to moderate decreases in renal function and show progression on subsequent biopsies. It is suggested that: 1) Focal global sclerosis is a disorder different from focal segmental sclerosis, presenting at an earlier age, responding to steroid therapy, and carrying a good prognosis. 2) Although focal segmental sclerosis is usually associated with NS, it can also present with only proteinuria and hematuria. Patients with this lesion do not respond to steroid therapy. Despite the fact that some patients maintain near-normal renal function over several years, all show histological deterioration.