Global Sclerosis Research Articles

Effects of aging on glomerular function and number in living kidney donors

To elucidate the pathophysiologic changes in the kidney due to aging, we used physiological, morphometric, and imaging techniques to quantify GFR and its determinants in a group of 24 older (≥ 55 years) compared to 33 younger (≤ 45 years) living donors. Mathematical modeling was used to estimate the glomerular filtration coefficients for the whole kidney (K(f)) and for single nephrons (SNK(f)), as well as the number of filtering glomeruli (N(FG)). Compared to younger donors, older donors had a modest (15%) but significant depression of pre-donation GFR. Mean whole-kidney K(f), renocortical volume, and derived N(FG) were also significantly decreased in older donors. In contrast, glomerular structure and SNK(f) were not different in older and younger donors. Derived N(FG) in the bottom quartile of older donors was less than 27% of median-derived N(FG) in the two kidneys of younger donors. Nevertheless, the remaining kidney of older donors exhibited adaptive hyperfiltration and renocortical hypertrophy post-donation, comparable to that of younger donors. Thus, our study found the decline of GFR in older donors is due to a reduction in K(f) attributable to glomerulopenia. We recommend careful monitoring for and control of post-donation comorbidities that could exacerbate glomerular loss.

A Molecular Profile of Focal Segmental Glomerulosclerosis from Formalin-Fixed, Paraffin-Embedded Tissue

Focal segmental glomerulosclerosis (FSGS) is a common form of idiopathic nephrotic syndrome defined by the characteristic lesions of focal glomerular sclerosis and foot process effacement; however, its etiology and pathogenesis are unknown. We used mRNA isolated from laser-captured glomeruli from archived formalin-fixed, paraffin-embedded renal biopsies, until recently considered an unsuitable source of mRNA for microarray analysis, to investigate the glomerular gene expression profiles of patients with primary classic FSGS, collapsing FSGS (COLL), minimal change disease (MCD), and normal controls (Normal). Amplified mRNA was hybridized to an Affymetrix Human X3P array. Unsupervised (unbiased) hierarchical clustering revealed two distinct clusters delineating FSGS and COLL from Normal and MCD. Class comparison analysis of FSGS + COLL combined versus Normal + MCD revealed 316 significantly differentially regulated genes (134 up-regulated, 182 down-regulated). Among the differentially regulated genes were those known to be part of the slit diaphragm junctional complex and those previously described in the dysregulated podocyte phenotype. Analysis based on Gene Ontology categories revealed overrepresented biological processes of development, differentiation and morphogenesis, cell motility and migration, cytoskeleton organization, and signal transduction. Transcription factors associated with developmental processes were heavily overrepresented, indicating the importance of reactivation of developmental programs in the pathogenesis of FSGS. Our findings reveal novel insights into the molecular pathogenesis of glomerular injury and structural degeneration in FSGS.

Progression of Glomerulonephritis to End-Stage Kidney Disease in a Cat with Nephrotic Syndrome

A percutaneous renal biopsy was performed on a 3-year-old female Japanese domestic cat with pleural effusion, mild azotemia, hypoalbuminemia, hypercholesterolemia, and proteinuria. Glomerular lesions included mild diffuse hypercellularity and numerous capsular adhesions with segmental sclerosis/hyalinosis of glomerular tufts. Electron microscopy revealed many subendothelial dense deposits with characteristic outer protrusion of glomerular basement membrane. Diffuse and global granular deposits of IgG and C3 were detected along the capillary walls. Tubulo-interstitial changes were mild at the time of biopsy, but progression of the disease was predicted because of the many capsular adhesions of the glomerular tufts. The cat was fed a prescription diet without any other specific or symptomatic therapy after renal biopsy, and died 43 weeks after the biopsy. At necropsy, extensive tubulo-interstitial fibrosis and mononuclear cell infiltration had developed throughout the cortex and outer medulla, and most glomeruli had extensive global sclerosis or obsolescence with less prominent depositions of IgG and C3.

Protocol biopsies for focal segmental glomerulosclerosis treated with plasma exchange and rituximab in a renal transplant patient

We discuss a renal transplant patient with focal segmental glomerulosclerosis (FSGS) treated with plasma exchange and rituximab. A 45-yr-old woman underwent cadaveric renal transplantation in May 2008. She had started hemodialysis support in 1991. Immediately after transplantation, massive proteinuria (1-5 g/d) appeared. Graft biopsy at one h showed minor glomerular abnormalities with partial foot process effacement on electric microscopy. Protocol biopsy at three months after transplantation for persistent proteinuria showed obvious FSGS under light microscopy. Plasma exchange and rituximab administration were subsequently initiated in August 2008, and proteinuria disappeared within a month after starting these treatments. Protocol graft biopsy one yr after transplantation (2009) showed increased global sclerosis and a decrease in segmental sclerosis. In addition, foot process effacement had recovered by one yr after transplantation. Plasma exchange and subsequent rituximab administration led to clinical remission of post-transplant FSGS with improvement in podocyte structure. Rituximab should be considered soon after several sessions of plasmapheresis in transplant patients with recurrent FSGS.

“Now You See It, Now You Don't”: Morphologic Variability Is a Confounder in Chronic Rejection/Graft Sclerosis

We read with great interest the recently published overview of Kwun and Knechtle (1) and the accompanying commentary of Terasaki (2). We are in strong agreement with both their opinions and share their frustration with the limited options available to delay the development of chronic rejection/graft sclerosis (CR/GS). As stated by Terasaki (2), there is an unquestionable evidence for a distinctive form of renal (cardiac and pancreatic) graft pathology associated with circulating donor-specific antibodies (DSA+), which relentlessly leads to CR/GS (3–5). Accordingly, we are observing active chronic antibody-mediated rejection (AMR) in more than 25% of our renal patients biopsied for graft dysfunction after the first year of posttransplantation. The main features are transplant glomerulopathy, CD4 positivity, multilayering of basal lamina in peritubular capillaries, parenchymal scarring, and DSA+ (3). Needles to say, subclinical AMR is also identified in some protocol biopsies performed at earlier times. Although routine evaluation of DSA and CD4 staining have helped to delineate the histologic features of AMR, the morphologic diagnosis continues to be problematic, in part because of the inconsistent staining for CD4 which similar to DSA may fluctuate overtime, spontaneously or in response to treatment interventions. Morphologic characterization of chronic AMR is also complicated by bouts of “acute” injury that occur on the background of “chronic” sclerosing changes. In fact, advanced cases of chronic AMR have extensive scarring and remodeling, including glomerular global and segmental glomerular sclerosis that makes an accurate morphologic diagnosis impossible in nephrectomies from these failed grafts. CD4 capillary staining may remain and gives a clue for the cause of graft failure. While acknowledging the importance of DSA in the development of CR/GS, it is important to emphasize that a significant proportion of stable and failing allografts lack features of AMR. In the past years, we have prospectively correlated morphology including electron microscopy with CD4 staining and DSA studies in single or serial biopsies performed 1 to 17 years posttransplantation (>250 patients). With this approach, we have found that at least 50% of patients lack any feature of chronic AMR but may have CR/GS that can be linked to other factors including plain ischemic injury, de novo or recurrent diabetic glomerular sclerosis, de novo or recurrent glomerulopathy often associated with postadaptive segmental sclerosis. The heterogeneous phenotype of CR/GS is, thus, most consistent with a variety of operating mechanisms, which are only beginning to be deciphered. The lack of “specific” pathologic findings in a proportion of cases may be discouraging to some, but in fact, this evidence strengthens the diagnostic significance of microvascular inflammatory and reparative responses typically associated with chronic DSA/AMR. In this area, diagnostic advances were only possible with the integration of morphologic, immunohistochemical, and serologic data. A similar comprehensive approach will be necessary to understand other processes leading to CR/GS. To achieve an accurate determination of the cause of graft failure, there should be concerted efforts to characterize all morphologic confounders (i.e., “idiopathic” thrombotic microangiopathy, hepatitis C-related glomerulonephritis), and all available data collected along the lifespan of the graft taken into account (i.e., infections such as polyomavirus BK nephritis). Systematic collection and analysis of data also incorporating a stratification of risk factors inherent to each specific case (i.e., retransplantation, diabetes mellitus, extended criteria donor) will assure successful incorporation of more advanced technologies such as gene profiling of biopsy samples (6). Although pathologic analysis continues to be crucial, isolated biopsy findings only represent snapshots of the eminently complex and dynamic long-term interactions between graft and host. Integration of morphology with contemporary and previous, clinical and laboratory data will help in understanding CR/GS. Cinthia B. Drachenberg John C. Papadimitriou Department of Pathology University of Maryland School of Medicine Baltimore, MD

Early-Onset Podocyte Injury and Glomerular Sclerosis in Osborne-Mendel Rats

Progressive glomerular injury associated with early-onset proteinuria was investigated in male Osborne-Mendel (OM) rats aged 5 to 20 weeks. Age-matched male Fischer 344 (F344) rats were used for comparison. OM rats developed mild hypertension and selective proteinuria (albuminuria) from 5 weeks of age, and non-selective proteinuria from 7 weeks of age. Light microscopy of OM kidney revealed hyaline droplets in the podocyte at 5 weeks of age and vacuolation of podocytes and adhesion of the capillary loop to the Bowman's capsule at 7 weeks of age. Segmental glomerulosclerosis developed in OM rats from 15 weeks of age, and global sclerosis appeared at 20 weeks of age. Desmin, a marker of podocye injury, was expressed in podocytes from 10 weeks of age, and the intensity of expression increased with age. Ultrastructurally, damage to podocytes such as effacement of foot processes, decreasing number of filtration slits, and rearrangement of the actin cytoskeleton were observed from 5 weeks of age in OM rat. Glomerular volume in OM rats increased with age and was consistently higher than in age-matched F344 rats. The number of WT-1-positive podocytes and vimentin-positive podocyte area were lower in OM rats and decreased with age. These findings suggest that glomerulonephropathy in male OM rats is associated with glomerular hypertrophy, progressive podocytopathy, and a reduction in podocyte number and area. Renal injury in OM rats was associated with development of early-onset proteinuria and was more progressive than in age-matched F344 rats.

Association of HLA-G gene promoter haplotype with childhood IgA nephropathy in the Korean population

Purpose: IgA nephropathy (IgAN) is the most commonly occurring form of chronic glomerulonephritis in pediatric cases. Human leukocyte antigen (HLA) genes have been implicated in various inflammatory and autoimmune diseases. The pre- sent study was conducted to investigate the association between 2 single nucleotide polymorphisms (SNPs) of the HLA-G gene and childhood IgAN. Methods: The authors analyzed and compared HLA-G gene SNPs (rs1736936 and rs2735022) in 174 patients with child- hood IgAN and in 438 healthy controls. In addition, IgAN patients were dichotomized and compared with respect to pro- teinuria ( 4 mg/m 2 /hour), the presence or absence of podocyte foot process effacement, and the presence of pa- thologically early and advanced disease markers such as interstitial fibrosis, tubular atrophy, or global sclerosis. Results :No significant SNP frequency differences were observed for the HLA-G gene between IgAN patients and the con- trol group. Moreover, no significantly associated SNP was observed with the presence of proteinuria, podocyte foot pro- cess effacement, or pathologically advanced markers. However, the haplotype, composed of rs1736936 and rs2735022, showed a significant association with the susceptibility to develop childhood IgAN (haplotype T/C: dominant model, P= 0.049; haplotype C/T: recessive model, P =0.030). Conclusion :Our results indicate that rs1736936 and rs2735022 as the HLA-G gene promoter haplotype might be asso- ciated with the susceptibility to develop childhood IgAN in the Korean population. (Korean J Pediatr 2010;53:548-553)

Association between polymorphisms in Interleukin-17 receptor A gene and childhood IgA nephropathy

2 /h, respectively) and the presence of pathological levels of biomarkers of diseases such as interstitial fibrosis, tubular atrophy, or global sclerosis. Results : No difference was observed between the SNP genotypes rs2895332, rs1468488, and rs4819553 between IgAN patients and control subjects. In addition, no significant difference was observed between allele frequency of SNPs rs2895 332, rs1468488, and rs4819553 between patients in the early and advanced stage of the disease. However, significant difference was observed between the genotype of SNP rs2895332 between patients with proteinuria (>4 mg/m 2 /h) and those without proteinuria (codominant model OR 0.36, 95% CI 0.19 0.66, - P <0.001; dominant model OR 0.35, 95% CI 0.17 0.69 - P =0.002; recessive model OR 0.12, 95% CI 0.01 1.06 - P=0.025). Conclusion : Our results indicate that the SNP in IL-17RA (rs2895332) may be related to the development of proteinuria in IgAN patients. (Korean J Pediatr 2010;53:215-221)

Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN).

In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Effects of radiotherapy upon progression of crescentic glomerulonephritis in rats

To study the effects of radiotherapy upon progression of crescentic glomerulonephritis in rats. Male SD rats were divided into three groups: (1) control (n=12), sham-operation; (2) crescentic glomerulonephritis (n=23), intravenously inject with nephrotoxic serum (NTS); (3) radiotherapy (n=55), a single low-dose irradiation of 0.5 Gy X-ray to both kidneys at Days 6, 13, 20 and 27 after NTS injection, and sacrificed at different time points among control and crescentic glomerulonephritis rats. Radiotherapy rats have received local kidney irradiation at Days 6, 13, 20 and 27 after bolus NTS injection and would be referred to as NTS7dRa1d, NTS14dRa1d, NTS21dRa1d and NTS28dRa1d, respectively. For NTS7dRa1d and NTS14dRa1d rats of radiotherapy, the levels of serum creatinine, glomerular hypercellularity, crescents and global sclerosis were significantly lower at Days 8 (P < 0.05), 15, and 22 post-irradiation as compared with group of crescentic glomerulonephritis of similar time intervals (P < 0.01). The extent of tubulointerstitial damage was also reduced, and radiotherapy associated histological improvements were accompanied by reduced macrophage infiltration in glomeruli and interstitium. The numbers of PCNA- and ED1-positive cells were reduced in the kidneys at Day 1 postirradiation in NTS7dRa1d and NTS14dRa1d rats as compared with group of crescentic glomerulonephritis at similar time intervals (P < 0.05). A larger number of TUNEL-positive cells were noted at Day 1 postirradiation in rats irradiated at Days 6 & 13 after NTS injection as compared with group of crescentic glomerulonephritis at similar time intervals (P < 0.05). With regards to immunostaining for macrophages ED1 and TUNEL, serial sections of irradiated nephritic kidney showed that fewer ED1-positive macrophages were stained for TUNEL. As evaluated expression of active caspases 3 & 7 was noted in irradiated kidneys as compared with the corresponding group of crescentic glomerulonephritis at similar time intervals. Western blot analysis showed marked increase in the expression of active caspase 3 & 7 in irradiated kidneys as compared with NTS injection only the expression of a marked increase in the expression of p53 protein, closely related to radiation-induced apoptosis, was also observed in irradiated kidneys as compared with NTS injection only. Radiotherapy inhibits the progression of experimental crescentic glomerulonephritis through inducing apoptosis by a p53-dependent pathway.

Interleukin-1 cluster gene polymorphisms in childhood IgA nephropathy

We have carried out a study with the aim of investigating the association between single nucleotide polymorphisms (SNPs) of the IL-1 gene cluster and childhood IgA nephropathy (IgAN). SNPs of the IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist (RN) genes (IL1A, IL1B, and IL1RN, respectively) were analyzed in 182 patients with childhood IgAN and in 500 healthy controls. The IgAN patients were also dichotomized and compared with respect to proteinuria (<4 mg and >or=4 mg/m(2) per hour, respectively), the presence or absence of podocyte foot process effacement, and the presence of pathologically early and advanced disease markers, such as interstitial fibrosis, tubular atrophy, or global sclerosis. Significant differences in SNP frequencies were observed for the IL1B and IL1RN genes (rs1143627, rs3917356, and rs1143633 in the IL1B gene, and rs928940, rs439154, and rs315951 in the IL1RN gene). Moreover, rs1143627, rs3917356, and rs1143633 of IL1B were found to be significantly associated with the presence of podocyte foot process effacement. Our results suggest that the IL1B and IL1RN genes are associated with increased susceptibility to IgAN in children. They also suggest that the development of proteinuria in IgAN is related to IL1A and that podocyte foot process effacement is associated with IL1B.

Clinical remission and pathological progression after tonsillectomy in a renal transplant patient with recurrent IgA nephropathy

We discuss a renal transplant patient with recurrent IgA nephropathy (IgAN) before and after tonsillectomy. A 36-year-old man started on hemodialysis support in 1996 due to biopsy-proven IgAN, living related renal transplantation was then performed in 1997. Six years after transplantation, the patient presented with microhematuria and proteinuria. Graft biopsy for these urinary abnormalities showed recurrent IgAN. Tonsillectomy was subsequently performed in December 2003, proteinuria remitted 6 months after the tonsillectomy and microhematuria disappeared three years later. Protocol graft biopsy was subsequently performed twice, at 2 yr after the tonsillectomy (2005) and 4 yr after (2008). Comparing the findings of the pre-tonsillectomy biopsy and the two post-tonsillectomy biopsies, an increase in mesangial cells and matrix in 2005, and an expansion of the mesangial matrix and proliferation of mesangial interposition in 2008. In addition, global sclerosis of glomeruli increased over time, the area of tubulointerstitial damage has extended as well. While the tonsillectomy led to clinical remission of recurrent IgAN, the chronicity progressed on these protocol biopsies. This is the first report of the efficacy and the limitations of tonsillectomy in a case of recurrent IgAN in a transplant patient.

Thiazide Effects and Adverse Effects

One of the longest-running debates in clinical medicine shows no sign of disappearing; just when it seems that thiazides have reassumed their role as front-line drugs to treat hypertension,1 new concerns emerge,2–4 leading some to question their role once again.5 Thiazides are effective antihypertensives with long track records and low cost. The major concerns about their use arise from their tendency to cause hypokalemia, impair glucose tolerance, increase serum cholesterol, and increase serum uric acid. Few medical controversies have generated as much heat, with well-established camps staking out positions that appear resistant to change.6–9 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the largest study of antihypertensive monotherapy ever performed,10 was intended to identify the best first-line treatment for high-risk hypertensive individuals; however, despite its size and the numerous resulting publications, its implications and authority continue to be disputed. The goal of this review is not take sides in this debate but rather to inject a distinct, and sometimes neglected, perspective; during the past 15 years, remarkable developments in molecular biology and human genetics have provided substantial insights into the pathogenesis of hypertension and mechanisms and adverse effects of diuretics. Diuretic proponents and antagonists alike often neglect these developments when addressing the topic; it is the purpose of this Brief Review to integrate these developments into the debate with the goal of generating questions that can be addressed scientifically. Thiazide diuretics were developed during the 1950s, when chemists and physiologists at Merck Sharpe and Dohme tested derivatives of sulfonamide-based carbonic anhydrase inhibitors, with the goal of discovering drugs that enhance the excretion of sodium with chloride rather than sodium bicarbonate.* Although these drugs lower arterial pressure effectively, the mechanisms have long perplexed investigators.11 Thiazides reduce cardiac output acutely by reducing extracellular …

The relation between inflammation and neurodegeneration in multiple sclerosis brains

Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.

The level of urinary secretory immunoglobulin A (sIgA) of patients with IgA nephropathy is elevated and associated with pathological phenotypes

Recent studies have demonstrated deposition of secretory immunoglobulin A (sIgA) in glomeruli of some patients with IgA nephropathy (IgAN). The aim of this study is to investigate the levels of urinary sIgA in IgAN patients with different pathological phenotypes and whether it could be used as a non-invasive biomarker for assessment of kidney injury in IgAN. Urine samples from 202 patients with IgAN were collected on the day of renal biopsy. Forty-eight fulfilled the histopathological criteria of Haas-I or II (group 1), 60 fulfilled Haas-III (group 2) and 94 patients fulfilled Haas-IV or V (group 3). Urine samples from 60 healthy sex- and age-matched volunteers with negative urinalysis were collected as normal controls. Urinary sIgA was detected by sandwich enzyme-linked immunosorbent assay and was corrected by urinary creatinine. In comparison with normal controls, the levels of urinary sIgA were significantly higher in IgAN [2.22 (0-43.82) microg/mg Cr versus 1.08 (0-16.49) microg/mg Cr, P < 0.001]. The levels of urinary sIgA were significantly higher in group 3 than that in group 2 and group 1 [3.54 (0-43.82) microg/mg Cr versus 1.63 (0-15.88) microg/mg Cr versus 0.91 (0-11.79), P < 0.001], and group 2 than group 1 (P = 0.014). The levels of urinary sIgA were associated positively with proteinuria (r = 0.443, P < 0.001), serum creatinine (r = 0.376, P < 0.001) and histopathological parameters, such as ratio of global sclerosis (r = 0.356, P < 0.001), ratio of total crescents (r = 0.339, P < 0.001) and ratios of cellular crescents (r = 0.231, P < 0.001). The levels of urinary sIgA were associated closely with histopathological phenotypes of IgAN and might be used as a non-invasive biomarker to evaluate kidney injury in IgAN.

Clinical phenotypes and natural progression for motor neuron disease: Analysis from an Australian database

From 1997 to 2003 we prospectively followed a cohort of ALS/MND patients. Patients were allocated to predetermined clinical phenotypes using the principles established in the modified El Escorial criteria. The date and region of symptom onset were carefully determined and their progression was scored using the Appel ALS rating scale. The four distinct clinical phenotypes: Global, Flail Arm, Flail Leg and Primary Lateral Sclerosis (PLS) demonstrated significantly different rates of progression and survival times. The Global ALS/MND phenotype can present with initial symptoms in any region and rapidly progresses to involve all segments, with symptoms due to a mixture of combined corticospinal tract and anterior horn cell dysfunction. The Global phenotype has the shortest survival and most rapid rate of disease progression. There was a significant difference in survival between Global bulbar onset and cervical onset disease but no significant difference in the rate of disease progression between the three Global subgroups as determined by the Appel/ALS rating scale. Flail patients had much slower rates of progression and significantly longer survival compared to the Global phenotype. Patients with Primary Lateral Sclerosis as expected progressed the slowest and survived the longest compared to the other clinical phenotypes. The utility of developing a method of assigning clinical phenotypes with similar survival and disease progression rates is discussed in relation to therapeutic trial design, practice benchmarking and clinico-pathological correlations.

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.

De-Novo&amp;nbsp; IgA Nephropathy and Cyclosporine Toxicity After Heart Transplantation

Introduction IgA nephropathy (IgAN) is the most common type of glomerulonephritis (GN) accounting for about 15%–20% of all GNs in Europe and 30%–40% in Japan but is less often observed in North-America (1,2). The diagnostic hallmark of IgAN is mesangial deposition of immunoglobulin A (IgA) often together with complement-3 (C3) in the glomeruli and some patients with IgAN may have increased levels of circulating immuno-complexes containing IgA. IgAN, initially considered to be a disease with benign prognosis, may eventually progress to end-stage-renal disease (ESRD) in 15%–40% of the cases (2,3,4). In order to predict outcome in patients with IgAN a grading of glomerular changes from kidney biopsies has been used (5). The etiology of IgAN is still not known but several observations point to some involvement of ethnic and genetic factors (6,7). Acute myocarditis (AM) accompanied with acute heart failure may need intensive care treatment and with a progressive course an early heart transplantation (HTx) might be offered if a suitable heartdonor is present. Different kinds of viruses may often cause AM and Coxsackie B-virus, Cytomegalovirus, Adenovirus, and Infl uenza A-virus, are accounting for most of the cases. End-stage renal failure (ESRF) is a well known late complication of HTx (8) with a poorer outcome than in other ESRF (9) subjects. ESRF may be related to hypertension regardless of their immunosuppressive regimen (9,10), or related to different infections, including sepsis, and to their treatments (9,10). However, calcineurin inhibitor nephrotoxicity (CIN) is the most recognized late renal complication after HTx (10,11). Different forms of de-novo GNs like membranous, membranoproliferative GN, and IgAN have been reported after solid organ transplantation (12,13). Immune-complex deposit glomerulopathy (15), and focal segmental glomerulosclerosis have been observed after HTx (10,14). Our case had acute myocarditis with rapid progressive heart failure needing a heart transplantation. Subsequently chronic renal failure developed and a kidney biopsy performed seven years after HTx confi rmed global glomerular sclerosis and IgA nephropathy.

Collapsing glomerulopathy presenting as the initial manifestation of systemic lupus erythematosus.

A 48-year-old African American female with a history of essential hypertension presented with fatigue of several weeks’ duration. Her only home medication was amlodipine. The patient denied illicit drug use. Apart from a purplish malar rash, physical examination was noncontributory. The patient did give a history of a photosensitive skin eruption on both arms in the past. Laboratory data included blood urea nitrogen 90 mg/dl, creatinine 8.6 mg/dl (baseline 0.9 mg/dl), platelet count 80 000, positive ANA with titer of 1:180, positive anti-double stranded DNA antibodies with titer of 140, C3: 80 mg/dl (normal 86–184), C4: 15 mg/dl (normal 20–59), C-reactive protein 1.7 mg/dl and urine protein excretion 8.6 g over 24 h. Systemic lupus erythematosus (SLE) was diagnosed taking into consideration the patient’s thrombocytopenia, proteinuria, significantly elevated antinuclear and anti-double stranded DNA antibody titers along with the malar rash and history of photosensitive eruption (hence meeting the minimum of four American College of Rheumatology criteria). A renal biopsy (Figure 1) revealed tubuloreticular inclusions and podocyte foot process effacement. No immune deposits were seen by immunostaining. There were a total of 19 glomeruli seen, 10 of which revealed obsolescence with global sclerosis, retraction of the tuft and Bowman’s space occupied by collagenous material. One glomerulus showed collapsing features including wrinkling and collapse of the basement membrane, confirming the diagnosis of collapsing glomerulopathy. The remaining eight glomeruli were normal. Tests for viral hepatitis, cytomegalovirus infection (CMV), parvovirus B19, human T-cell lymphotrophic virus infection 1 (HTLV-1) and human immunodeficiency viruses (HIV) were negative. The patient’s condition im

Signaling pathways modulated by fish oil in salt-sensitive hypertension

Although many studies have indicated that fish oil (FO) improves cardiovascular risk factors and reduces histopathological manifestations of injury in experimental renal injury models, potential mechanisms underlying this protective effect have not been adequately defined. The objective of this study was to identify potential signaling pathways that confer protection in the Dahl rat model of salt-sensitive hypertension. Male Dahl salt-sensitive rats (n = 10/group) were provided with formulated diets containing 8% NaCl, 20% protein, and 25% FO or 25% corn oil (CO) for 28 days. FO reduced blood pressure (-11% at 4 wk; P < 0.05), urine protein excretion (-45% at 4 wk; P < 0.05), plasma cholesterol and triglyceride levels (-54%, P < 0.001; and -58%, P < 0.05), and histopathological manifestations of renal injury, including vascular hypertrophy, segmental and global glomerular sclerosis, interstitial fibrosis, and tubular atrophy. Interstitial inflammation was significantly reduced by FO (-32%; P < 0.001), as assessed by quantitative analysis of ED1-positive cells in sections of the renal cortex. FO reduced tubulointerstitial proliferative activity, as assessed by Western blot analysis of cortical homogenates for PCNA (-51%; P < 0.01) and quantitative analysis of Mib-1-stained sections of the renal cortex (-42%; P < 0.001). Decreased proliferative activity was associated with reduced phospho-ERK expression (-37%; P < 0.005) and NF-kappaB activation (-42%; P < 0.05). FO reduced cyclooxygenase (COX)-2 expression (-63%; P < 0.01) and membrane translocation of the NADPH oxidase subunits p47(phox) and p67(phox) (-26 and -34%; P < 0.05). We propose that FO ameliorates renal injury in Dahl salt-sensitive rats through the inhibition of ERK, decreased NF-kappaB activation, inhibition of COX-2 expression, and decreased NADPH oxidase activation.