Anti-RNA polymerase III antibody-associated scleroderma renal crisis in a patient with limited cutaneous systemic sclerosis: A case report.

A 69-year-old Japanese man was presented with hypertensive crisis. Renal histology revealed malignant nephrosclerosis, including an onion skin pattern with fibrinoid necrosis of the small arteries from arterioles up to interlobular arteries. Immunological investigation clarified positive anti-RNA polymerase (RNAP) III antibody, and limited cutaneous systemic sclerosis (Lc SSc) was diagnosed by skin biopsy as the underlying disease causing scleroderma renal crisis (SRC). Angiotensin covering enzyme (ACE) inhibitor therapy and calcium antagonist were effective for his renal condition. Although an association between SRC and anti-RNAP III antibody has already been reported in patients with diffuse cutaneous SSc (Dc SSc), this case indicates that SRC with hypetensive emergency with malignant nephrosclerosis can also be diagnosed on patients with Lc SSc patients by the examination of anti-RNAP III antibody.

HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury.

Previous studies have indicated that macrophage phenotype diversity is involved in the progression of renal fibrosis. However, the factors facilitating M1 or M2 phenotypes and the function of these polarized macrophages in kidney injury and fibrosis remain largely unknown. In the present study, we found that macrophages accumulated in the kidney interstitium exhibited mainly as the M1 phenotype at the early stage of unilateral ureter obstruction (UUO). High-mobility group box 1 (HMGB1) protein expressed and released from tubular epithelial cells and interstitial macrophages was essential for the M1 macrophage transition. HMGB1 significantly induced the expression of the M1 marker inducible nitric oxide synthase while decreasing the M2 marker IL-10 in macrophages. Moreover, a glycyrrhizic acid derivative, a blocker of HMGB1 release, reduced UUO-mediated kidney injury and ameliorated UUO-induced renal fibrosis. Interestingly and importantly, UUO caused a low pH value in the urine accumulated in the obstructed ureter, and the acidified urine induced HMGB1 release from tubular epithelial cells and macrophages in vitro. Our data demonstrate that HMGB1 is an essential contributor in facilitating M1 polarization at the early stage of UUO. Inhibition of HMGB1 release may alter macrophage phenotype and contribute to the protection of kidney tissue from injury and fibrosis.

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats.

Tubulointerstitial macrophage infiltration is a hallmark of chronic kidney disease involved in the progression of renal fibrosis. Pirfenidone is a newly identified antifibrotic drug, the potential mechanism of which remains unclear. The aim of this study was to investigate the effects of pirfenidone on M1/M2 macrophage infiltration in nephrectomized rats. Nephrectomized rats were treated with pirfenidone by gavage for 12 wk. Twenty-four hour urinary protein, N-acetyl-ß-D-glycosaminidase (NAG) activity, systolic blood pressure, and C-reactive protein were determined. Paraffin-embedded sections were stained for CD68, CCR7, and CD163 macrophages. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), as well as M1 and M2 macrophages secretory markers, were evaluated by real-time RT-PCR and Western blotting analysis. Pirfenidone significantly improved the elevated proteinuria and NAG activity from week 2 onward after surgery. Pirfenidone attenuated interstitial fibrosis and decreased expression of fibrotic markers including transforming growth factor-ß(1), connective tissue growth factor, α-smooth muscle actin, fibronectin, and fibroblast-specific protein-1. Pirfenidone significantly decreased the infiltrating macrophages. The number of M1 and M2 macrophages was significantly lower after pirfenidone treatment. MCP-1 and MIP-1α were increased in nephrectomized rats at mRNA and protein levels. Pirfenidone treatment significantly inhibited their expression. The TNF-α, IL-6, and nitric oxide synthases-2 expressed by M1 macrophages were increased in nephrectomized rats, and pirfenidone significantly attenuated their expression. Pirfenidone treatment also significantly decreased arginase-1, dectin-1, CD206, and CD86 expressed by M2 macrophages. Thus pirfenidone inhibits M1 and M2 macrophage infiltration in 5/6 nephrectomized rats, which suggests its efficacy in the early and late periods of renal fibrosis.

Human leukocyte antigens as a risk factor for the primary diseases leading to end stage renal disease in Egyptian patients.

The number of patients with end stage renal disease (ESRD) is increasing considerably worldwide. The incidence of ESRD is likely to be higher than that reported from the developed world, with diabetic nephropathy, hypertension and chronic glomerulonephritis being the most common causes in Egypt. The aim of the present study is to investigate the Human leukocyte antigens [HLA-A,-B and -DRB1 antigens] as a risk factor for the primary diseases leading to ESRD in Egyptian patients. Our study included a total of 457 individuals comprising 207 ESRD patients and 250 healthy controls were enrolled into the study. Class I [HLA-A and-B] typing was performed by complement-dependent cytotoxicity (CDC) method, while class II HLA-DRB1 typing was performed by low resolution polymerase chain reaction (PCR)-sequence-specific oligonucleotide probe [PCR-SSOP]. We found that the most common primary disease groups leading to ESRD classified as Diabetic nephropathy, hypertensive nephrosclerosis and chronic glomerulonephritis. HLA-A2, -B8 and DRB1*3 and HLA-DRB1*11 significantly correlated with diabetic nephropathy, respectively. B8-DR3 haplotype is susceptible to DM. In, conclusion, determination of HLA-A,-B and -DRB1 as a risk factor for primary diseases leading to ESRD might be beneficial in preventing progression to ESRD and recurrence of the primary disease post-transplantation.

Heme oxygenase-1 deficiency promotes epithelial-mesenchymal transition and renal fibrosis.

Induction of heme oxygenase-1 (HO-1) is associated with potential antifibrogenic effects. The effects of HO-1 expression on epithelial-mesenchymal transition (EMT), which plays a critical role in the development of renal fibrosis, are unknown. In this study, HO-1(-/-) mice demonstrated significantly more fibrosis after 7 d of unilateral ureteral obstruction compared with wild-type mice, despite similar degrees of hydronephrosis. The obstructed kidneys of HO-1(-/-) mice also had greater macrophage infiltration and renal tubular TGF-beta1 expression than wild-type mice. In addition, the degree of EMT was more extensive in obstructed HO-1(-/-) kidneys, as assessed by alpha-smooth muscle actin and expression of S100A4 in proximal tubular epithelial cells. In vitro studies using proximal tubular cells isolated from HO-1(-/-) and wild-type kidneys confirmed these observations. In conclusion, HO-1 deficiency is associated with increased fibrosis, tubular TGF-beta1 expression, inflammation, and enhanced EMT in obstructive kidney disease. Modulation of the HO-1 pathway may provide a new therapeutic approach to progressive renal diseases.

Hypertensive nephrosclerosis: update.

UNLABELLED: PURPOSE OF VIEW: A major clinical trial and a meta-analysis completed within the past year addressed the issue of renal disease progression after blood pressure-lowering treatment in patients with hypertension and diminished renal function. Important human and animal studies have addressed mechanistic issues regarding renal disease progression. These advances warrant detailed discussion. RECENT FINDINGS: The African American Study of Kidney Disease and Hypertension Study Group trial found that an angiotensin-converting enzyme inhibitor was superior to a calcium antagonist or beta-blocker in ameliorating renal disease progression in African-Americans. An attempt to show an advantage of lowering blood pressure to less than 130/80 compared with 140/90 mmHg showed no additional benefit. However, a meta-analysis of 2000 non-diabetic hypertensive patients suggested that lower blood pressures are beneficial, particularly in individuals with proteinuria. An autopsy study of hypertensive and normotensive individuals dying in motor vehicle accidents supported the theory that hypertensive individuals have fewer, albeit larger, glomeruli than normotensive individuals. An animal study in sheep showed similar findings in sheep born to dams given dexamethasone compared with placebo. Animal studies involving stress, immunity, and cytokines shed further light on the mechanisms. The transfer of Smad7 ameliorated renal damage in rats with ureteral obstruction and fibrosis. SUMMARY: Guidelines suggest prescribing angiotensin-converting enzyme inhibitor or angiotensin 1 receptor blocker therapy to all patients with decreased renal function and hypertension with or without diabetes. The possibility that essential hypertension involves reduced glomerular numbers received support, as well as the theory of prenatal imprinting. Progress is being made regarding basic mechanisms and novel therapies.

Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury.

BACKGROUND: We investigated whether monocyte chemoattractant protein-1 (MCP-1) is expressed in hypertensive nephrosclerosis, and tested the effect of angiotensin II type 1 receptor blockade on MCP-1 expression and macrophage (MPhi) infiltration. METHODS: Rats with two-kidney, one-clip (2K1C) hypertension with and without treatment with the angiotensin II type 1 receptor antagonist valsartan (3 mg/kg/day) were studied. In these animals as well as in spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP), hypertensive mRen-2 transgenic rats (TGR), and respective control strains, MCP-1 expression in the kidney was investigated by Northern and Western blots and by immunohistochemistry. Glomerular and interstitial MPhis were counted. RESULTS: In the nonclipped kidney of 2K1C rats, MCP-1 expression was elevated at 14 and 28 days when significant MPhi infiltration was present. MCP-1 was localized to glomerular endothelial and epithelial cells, interstitial and tubular cells, MPhis, and vascular smooth muscle cells. A similar pattern of MCP-1 staining was present in TGR kidneys, whereas MCP-1 expression was not increased in SHR and SHR-SP. Valsartan reduced but did not normalize blood pressure, blocked the induction of MCP-1 protein in 2K1C kidneys, and decreased interstitial MPhi infiltration significantly. CONCLUSION: MCP-1 expression is increased in angiotensin II-dependent models of hypertensive nephrosclerosis and is temporally and spatially related to MPhi infiltration. The angiotensin II type 1 receptor mediates the induction of MCP-1.

Generation of superoxide anions during phagocytosis by monocytes of uremic patients.

The phagocytic activity of monocytes from 15 uremic patients was estimated by the superoxide anion test. There was a significant decrease in the ability of monocytes from these patients to produce superoxide anions in comparison with monocytes obtained from healthy subjects. Addition of urea to monocytes from healthy subjects caused a marked reduction in their ability to produce superoxide anions, while addition of creatinine did not cause any effect. Monocytes from patients with renal failure of glomerular origin were found to produce less superoxide anions than those from patients with other types of renal diseases.

Hyaline arteriolar nephrosclerosis. Immunofluorescence findings in the vascular lesions.

Of 536 renal specimens examined by direct immunofluorescence in the past 2 years, 153 contained vascular deposits of C3 without associated immunoglobulin or fibrin deposition. Excluding vasculitides, renal transplants, and outside cases with inadequate clinical data, 110 were selected for further study. Light microscopy showed periodic acid-Schiff-positive hyaline vascular deposits in 83 cases, and large electron-dense deposits were identified by electron microscopy in 47 cases. Fifty-one patients had immunologic glomerular disease in addition to hyaline arteriolar nephrosclerosis. Albumin, transferrin, and alpha-2 macroglobulin were not detected in the vessel walls of several selected cases so tested, indicating that passive diffusion probably does not explain C3 deposition. However, properdin was present in 11 of 14, and C4 in two of 11. The mechanism for this association between C3 and properdin deposition and hyaline arteriolar nephrosclerosis is not clear at present, but our findings suggest possible involvement of the alternative pathway of the complement system.

Nephrotic syndrome and focal glomerular sclerosis in aging man.

Focal glomerular sclerosis (FGS) with the nephrotic syndrome is a disecades. Less than 2% of reported patients are older than 60 years of age, and to our knowledge no patients over 70 years of age have been described. The present report documents with renal biopsies the occurrence of FGS and the nephrotic syndrome in 4 patients with an average age of 70 years, 3 being septuagenarians. We suggest that FGS in these patients may represent a disease of senescence, and that FGS in younger patients may result from accelerated glomerulotubular senescence.

[Immunohistological findings in non-glomerulonephritic renal disease (author's transl)]. / Immunhistologische Befunde bei nicht-glomerulonephritischen Nierenerkrankungen.

Immunohistological study of 123 kidney biopsies of non-glomerulonephritic kidney diseases showed that deposits of immunoglobulins are found more often in cases of malignant than in cases of benign nephrosclerosis. Primary malignant nephrosclerosis is mostly associated with glomerular deposits of immunoglobulins. Positive immunohistological findings are frequent in cases of diabetic glomerulosclerosis, mainly within glomeruli, but also in tubular basement membranes and Bowman's capsule. In cases of glomerular amyloidosis we see cloudy-bandlike deposits, but are unable to differentiate cases with or without the nephrotic syndrome. If we consider an immunopathogenetic mechanism for the diseases discussed in terms of the present findings, it seems possible for primary malignant nephrosclerosis as well as for certain glomerular changes associated with acute renal failure or rejection of transplants. In diabetic glomerulosclerosis (apart from special forms with perimembranous lesions) and glomerular amyloidosis, we consider such a mechanism to be unlikely. By separating the non-glomerulonephritic diseases into different types of deposits we found pictures that correspond with immunocomplex diseases. Pictures resembling anti-basement membrane diseases have not been seen. Characteristic patterns of deposits were not found, thus immunohistology is without additional diagnostic value in the field of non-glomerulonephritis disease.

Quantitative studies of immunoglobulin deposition in the kidney, glomerular cell proliferation and glomerulosclerosis in NZB/NZW F1 hybrid mice.

Using the NZB and NZB/NZW F1 (B/W) hybrid mouse as a model for systemic lupus erythematosus, an effort has been made to quantitate: (1) immune complex deposition in the glomeruli by immunofluorescent staining of immunoglobulin, (2) glomerular cellular proliferation by radioautographic measurement of [3H]Tdr incorporation into the glomerular cells in vivo, and (3) glomerular scarring by PAS staining. The relationship between these changes and increasing age has been examined. By radioautography it was observed that dividing glomerular cells were labelled in vivo after injection of [3H]Tdr. This provided a reproducible measure of the proliferative process in the nephritis of B/W mice. In C57B1/6J and CBA/J mice, which have a low incidence of glomerular disease, little change in the amount of glomerular cell proliferation was observed with increasing age. The NZB strain of animals showed a somewhat increased level of proliferation but this did not increase with age. In striking contrast, glomerular cell proliferation in the B/W mice increased rapidly with age. The earliest change observed in the kidney was the deposition of immunofluorescent material in the mesangium and glomerular capillary basement membrane beginning between 3 and 5 months of age and reaching a peak at 9 months. Increase in glomerular cell proliferation began about 2 months after the onset of immune complex deposition but also reached a maximum at 7 months. Glomerular sclerosis was the last change to appear and continued after the other two parameters measured has begun to decline. These data suggest that the deposition of immune complexes in the glomerulus may be an important triggering mechanism for renal cell proliferation and glomerulosclerosis in the B/W mouse. The techniques described would provide a sensitive and reproducible quantitative method for analysing the differential effects of various types of treatment of immune complex nephritis in animals.

Malignant nephrosclerosis during pregnancy and in the postpartum period (the uremic hemolytic syndrome).

Histologic, immunohistologic, and ultrastructural features are presented of two cases with malignant nephrosclerosis during pregnancy. Primary malignant nephrosclerosis emerges as a clinical entity which can be distinguished from toxemia of pregnancy in the midtrimester and post partum. The first description of malignant nephrosclerosis dates from 40 years ago, but only a few cases were reported associated with pregnancy. Although disseminated intravascular coagulation seems involved, the morphology is different from that of toxemia. Malignant nephrosclerosis reveals a close similarity to the hemolytic uremic syndrome. Early diagnosis by renal biopsy and proper treatment may prevent a lethal outcome due to progressive failure.

Molecular size of IgG in patients with focal glomerulosclerosis.

Nineteen patients with focal glomerulosclerosis and with anomalously high clearance of IgG into the urine have been investigated by G.200 column chromatography. The findings are compared with normal sera, with 14 patients with minimal change disease and with 12 patients with proliferative glomerulonephritis. No significant reduction in the molecular size of IgG was found as compared with normal sera and the other diseases in 18 of the patients. In patients with minimal change disease and focal glomerulosclerosis an increased proportion of the IgG eluted in the void volume

Mesangial lesions and focal glomerular sclerosis in the aging rat.

The pathogenesis of focal glomerular sclerosis (FGS) and its relation to proteinuria and idiopathic nephrotic syndrome are unknown. Urine protein excretion in Sprague-Dawley rats increased with age. Fifty per cent of 12-month and 90 per cent of 24-month-old animals were proteinuric (greater than 20 mg. per day). Heavily proteinuric old rats manifested biochemical changes characteristic of nephrotic syndrome without significant loss of renal function. Three-month, 6-month, and nonproteinuric 12-month-old animals had mesangial deposits of IgM in occasional lobules of some glomeruli and slight mesangial hyperplasia. Four proteinuric 12-month-old rats had diffuse 4+ deposits of IgM in the mesangium of most glomeruli, basement membrane thickening and epithelial cell foot process fusion without FGS. The mesangial IgM deposits eluted in acid buffer and did not fix complement. Six proteinuric 12-month-old rats had focal and segmental areas of glomerular sclerosis with adhesions to Bowman's capsule, foamy cells, intraluminal eosinophilic deposits and capillary wall wrinkling and collapse. These lesions were more advanced in 24-month-old animals. Nonproteinuric 24-month-old rats did not have detectable FGS. Mesangial uptake of colloidal carbon was normal in proteinuric and nonproteinuric animals without FGS. Mesangial uptake of colloidal carbon was normal in proteinuric and nonproteinuric animals without FGS and reduced in proteinuric animals with FGS. In the aging rat the development of proteinuria and mesangial IgM deposition apparently precede development of a focal sclerotic glomerular lesion with histologic and ultrastructural features similar to FGS in man. The generalized impairment of mesangial phagocytic function in proteinuric rats with FGS suggests that this lesion may result from mesangial overload and dysfunction consequent to the persistent increase in glomerular permeability and proteinuria.

Focal and segmental glomerular hyalinosis and sclerosis in the rat.

A glomerular disease spontaneously developing in Wistar rats was studied by light and electron microscopy and by immunofluorescence techniques. The disease is characterized by the local subendothelial deposition of hyaline material leading to increase of mesangial matrix and the development of adhesions. Immunofluorescence shows deposition of complement and IgM and to a lesser degree also of IgG in these lesions. There is a constant relationship of these early changes with the vascular pole of the glomerulus. It is confirmed that female rats are resistent to the disease as are male rats fed a sodium-deficient diet. A higher protein excretion was found in normally fed male rats as compared to female rats and to rats on a sodium-deficient diet. These differences already existed before the normally fed male rats developed glomerular disease. From these studies it is suggested that an appropriate name for this disease would be focal and segmental glomerular hyalinosis and sclerosis and that hemodynamic factors could be an important etiologic mechanism. The histopathology of the disease bears a striking resemblance to focal sclerosing glomerulopathy with segmental hyalinosis sometimes found in kidneys of patients with an idiopathic nephrotic syndrome.

[Immunohistological findings in diffuse mesangial sclerosis associated with the nephrotic syndrome of infancy (author's transl)]. / Immunohistologische Untersuchungen bei der diffusen mesangialen Sklerose mit nephrotischem Syndrom im Säuglingsalter

A 10-month-old infant developed a steroid resistant nephrotic syndrome. The renal biopsy revealed diffuse mesangial sclerosis of the glomerula. The child died from interstitial pneumonia 3 months after onset of the renal symptoms. Post mortem, the glomerular changes were diffuse but prominent in certain segments of the glomeruli. The immunohistological examination showed granular deposits of IgM and C3 in the mesangium and in the subendothelial region of the basement membrane. These findings are compatible with the hypothesis that diffuseal sclerosis is caused by glomerular deposition of immune complexes.

Protein overload nephropathy in rats with unilateral nephrectomy. A correlative light immunogluorescence and electron microscopical analysis.

We wish to determine what cellular and functional alterations are associated with the development of glomeruloscierosis when rats with one kidney are fed an excess of salt or protein. Rats with one kidney are more likely to develop pronteinuria and glomerulosclerosis than control animals. Blood pressure recordings indicate that proteinuria and glomerulosclerosis occur before hypertension is evident. Fluorescent antibody studies disclose that albumin accumulates in the epithelial cells of glomeruli and tubules. Ultrastructural examination shows that vacuolozation of epithelial cells and basement membrane thickening precede the sclerotic collapse of capillary loops. Increased concentrations of sodium or urea that are found in urines of these rats favor the point of view that an elevation of solute load when combined with a reduction of renal mass will on some unknown manner accelerate the deterioration of glomeruli.