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Background: JC polyomavirus (JCPyV)-associated nephropathy (JCPyVAN) is a severe, but rare complication in adult renal transplant (RTx) recipients. Related data in pediatric patients are scarce., Methods: Based on the CERTAIN Registry, we therefore performed a multi-center, retrospective study on the JCPyV antibody status, prevalence of JCPyV replication, and its associated disease in 139 pediatric RTx recipients (mean age, 8.5 ± 5.3 years). JCPyV DNA in plasma and/or urine was measured by quantitative PCR at a median time of 3.2 (IQR, 0.3-8.1) years post-transplant., Results: 53.2% of patients were JCPyV-seronegative prior to transplantation; younger age was associated with JCPyV seronegativity. 34/139 (24.5%) patients post-transplant showed active JCPyV replication in either urine (22.0%), plasma (13.4%), or both (7.6%). JCPyV viremia occurred significantly (p < 0.001) more often in patients with viruria (34.6%) than in those without (7.6%), but 7/118 (5.9%) had isolated viremia. High-level viruria (> 10 7  copies/mL) was found in 29.6% of viruric patients. A higher net state of immunosuppression constituted an independent risk factor for JCPyV replication both in urine and plasma (OR 1.2, p < 0.02). Male patients tended to have a higher risk of JCPyV viremia than females (OR 4.3, p = 0.057). There was one male patient (0.7%) with JCPyVAN 7 years post-transplant, which resolved after reduction of immunosuppressive therapy. No patient exhibited progressive multifocal leukoencephalopathy., Conclusions: This first multi-center study on JCPyV in pediatric renal transplant recipients shows that JCPyV replication is common (24.5%), with strong immunosuppression being a significant risk factor, but associated nephropathy is rare.

Background: Renal sarcoidosis (RS) is a possible manifestation of systemic sarcoidosis. The clinical presentation can range from asymptomatic individuals up to acute renal failure with the necessity of renal replacement therapy. The definite diagnosis must be established by renal biopsy., Objectives: Demonstration of clinical characteristics and effectiveness of steroid treatment., Methods: We present a single center study of 27 patients with histologically proven RS. Firstly, we elaborate on descriptive features such as extra-renal organ involvement, calcium levels, renal function, proteinuria and histological subtypes and provide an histological assessment of renal damage. Secondly, we present follow-up data over a period of 2 years or more., Results: Non-granulomatous tubulointerstitial nephritis (ngIN) was the most common histological entity (44%), followed by granulomatous IN (GIN, 30%), IgA-GN (26%) and nephrocalcinosis (11%). Under treatment with oral prednisone mean eGFR significantly improved from 38 ± 21 ml/min to 57 ± 26 ml/min and proteinuria decreased from 981 ± 304 mg/24 hrs to 176 ± 77 mg/24 hrs at the end of follow-up. In total, 62.5% of patients responded to therapy., Conclusions: We demonstrated that GIN is more often associated with advanced stages of renal insufficiency than any other histological manifestation of RS. Furthermore, prednisone therapy is effective in improving eGFR and in reducing total urinary protein secretion. We suggest that the key prognostic factor for renal survival in RS is the early response to treatment.

Background: Henoch-Schönlein purpura (HSP) is a fairly common disease in children and adolescents. There are only limited data available for adults., Methods: A retrospective analysis was conducted to study renal manifestations in patients with HSP treated in our institution between 1982 and 2007. We divided our adult cohort according to age - under or over 60 years - to examine differences in elderly patients., Results: HSP was identified in 2.2% of patients referred to us for kidney biopsy. Purpuric lesions and renal involvement were found in all patients. An important triggering factor for the development of HSP in our series was chronic alcohol intake. Forty percent of our patients fulfilled the WHO criteria for alcoholics. Renal involvement was particularly prominent in patients over 60 years of age. At disease onset, estimated glomerular filtration rate (eGFR) was 63% lower in the elderly. Within a median follow-up of 8 years, renal function was significantly better in younger adults than in the elderly. 32% of the elderly have shown Modification of Diet in Renal Disease (MDRD) < 20 ml/min/1.73 m2 in contrast to only 7% in patients < 60 years. Furthermore, significantly more elderly patients reached end-stage renal failure., Conclusion: The data indicate that renal manifestation of HSP in the elderly is severe and its outcome relatively poor, and worsens when compared to patients < 60 years.

Retinoids are anti-proliferative and anti-inflammatory compounds. We had previously shown that retinoids alleviate kidney damage in acute models of renal disease. We now examined whether retinoids are also effective in a chronic renal ablation model. Subtotally nephrectomized rats (SNx; two-third ablation) were compared to sham-operated controls (sham). SNx rats were administered either 10 mg/kg b.w. (low dose, LD) or 40 mg/kg b.w. (high dose, HD) isotretinoin or vehicle (n = 10 per group). The experiment was terminated after 16 weeks. Systolic blood pressure was significantly higher after SNx compared to sham but lower in SNx with LD isotretinoin (vs. SNx + vehicle). Compared to SNx + vehicle, SNx + LD isotretinoin had lower glomerular cell numbers, less glomerular hypertrophy and sclerosis, and less interstitial expansion. Morphological improvement in SNx + LD isotretinoin was accompanied by improvement in creatinine clearance and reduced urinary albumin excretion. In contrast, HD isotretinoin caused aggravation of renal damage with fibrinoid necroses of vessels and elevated urinary albumin excretion despite lower blood pressure. The dichotomous effects of isotretinoin are at least in part due to time- and dose-dependent alterations of transforming growth factor beta1 and collagen IV gene expression as also suggested by cell-culture studies in vascular smooth muscle cells. In addition, isotretinoin affected the systemic and the renal renin-angiotensin system (which was further analyzed in a model of angiotensin II infusion of the rat). Isotretinoin failed to cumulate at LD but cumulated at HD in SNx. We conclude that LD isotretinoin attenuates progressive renal damage, whereas HD isotretinoin cumulates and aggravates renal damage independent of blood pressure reduction.

Because calcineurin inhibitor (CNI)-induced nephrotoxicity contributes significantly to late renal allograft loss, sirolimus (SRL)-based, CNI-free maintenance immunosuppression has been advocated, but data in the pediatric population are scarce. We therefore analyzed the efficacy and safety of an SRL-based immunosuppressive regimen plus mycophenolate mofetil (MMF) and corticosteroids vs. CNI minimization (mean dose reduction by 39%) plus MMF and corticosteroids in 19 pediatric recipients with biopsy-proven CNI-induced nephrotoxicity in a single-center case-control study. In the SRL group, we observed, one yr after study entry, an improvement of glomerular filtration rate (GFR) by 10.3 +/- 3.0 mL/min/1.73 m2 (p < 0.05 vs. baseline) in seven of 10 patients and a stabilization in the remaining three, while in the CNI minimization group GFR improved by 17.7 +/- 7.1 mL/min/1.73 m2 (p < 0.05) in six of nine recipients and stabilized in the remaining three. No patient in either group experienced an acute rejection episode. The main adverse event under SRL therapy was a transient hyperlipidemia in 70% of patients. In pediatric renal transplant recipients with declining graft function because of CNI-induced nephrotoxicity, CNI withdrawal and switch to SRL-based therapy or CNI minimization are associated with a comparable improvement of GFR after 12 months of observation.

Background: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown., Methods: In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow., Results: In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy., Conclusion: Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.

Introduction: Sarcoidosis is an immunemediated disease of unknown cause, characterized by noncaseating epithelioid granulomas, affecting multiple organs. Clinically apparent renal involvement is rare and has been documented mostly as case reports. The incidence of renal involvement ranges from 3-23% with a wide spectrum of abnormalities., Aim: The aim of this study was to ivestigate the renal involvement in patients with sarcoidosis., Results: From 1995 to 2002 we diagnosed 46 patients with sarcoidosis. Fifteen patients suffered from acute sarcoidosis with arthritis, mediastinal adenopathy and erythema nodosum (Löfgren's-syndrome). Thirty-one patients had chronic sarcoidosis with organ involvement, such as granulomatous hepatitis, uveitis and pulmonary sarcoidosis. In 15 patients we found renal abnormalities, 10 patients underwent kidney biopsy. Six patients had nephrocalcinosis, 2 patients granulomatous interstitial nephritis, one patient interstitial nephritis without granuloma, and 1 patient suffered from IgA-glomerulonephritis. In 2 patients we found a combination of granulomatous interstitial nephritis either with nephrocalcinosis or with IgA-glomerulonephritis. In all patients the serum creatinine decreased after treatment with corticosteroids., Conclusion: In our retrospective analysis we found renal abnormalities in about 48% of patients with chronic sarcoidosis, but never in patients with acute sarcoidosis (Löfgren's syndrome). We conclude that kidney involvement in chronic sarcoidosis is more frequent than previously reported.

The endothelin (ET) system has been studied extensively in experimental models of progressive chronic renal disease, but there is limited information regarding the ET system in renal patients. First, the expression of human ET-1, as well as ET receptor type A (ET-R(A)) and ET-R(B), was studied in 26 renal biopsies from patients with different renal diseases. Gene expression was assessed by quantitative reverse transcription-PCR. Second, ET-1 and ET-R(B) protein expression and localization were examined, by immunohistochemical analyses, among a homogeneous cohort of 16 patients with IgA nephropathy and different degrees of proteinuria. ET-R(B) mRNA expression was threefold higher among patients with higher-grade proteinuria [> or =2 g/24 h, n = 10; OD ratio (ODR), i.e., wild-type/mutant mRNA ratio, 1.81 +/- 0.3], compared with patients with lower-grade proteinuria (<2 g/24 h, n = 8; ODR, 0.63 +/- 0.1; P < 0.01) or control subjects (n = 9; ODR, 0.57 +/- 0.1; P < 0.01). ET-1 gene expression was significantly higher among patients with higher-grade proteinuria, compared with patients with lower-grade proteinuria (P < 0.01) or control subjects (P < 0.05). ET-R(A) mRNA expression was not different among the groups. Patients with higher-grade proteinuria who were receiving angiotensin-converting enzyme inhibitors exhibited significantly (P < 0.05) lower ET-1 and ET-R(B) mRNA expression, which was comparable to that of control subjects. By using immunohistochemical analyses, an association between proteinuria and expression of ET-1 and ET-R(B) in proximal tubular epithelial cells and of ET-1 in glomeruli was confirmed in the separate cohort of patients with IgA nephropathy. It is concluded that the increased ET-R(B) and ET-1 mRNA and protein expression observed in animal models of renal disease is also demonstrable among patients with renal disease and high-grade proteinuria.

Renal granulomas are a relatively infrequent finding in the kidney biopsy. They have been described in a number of syndromes such as Wegener's granulomatosis, anti-GBM glomerulonephritis, and sarcoidosis, and are commonly believed to be indicative of a fulminant clinical course. In leading textbooks, diverse definitions of renal granulomas are presented, which has led to controversies in identifying them. This, in combination with their rare occurrence, makes it difficult for the general pathologist to identify them. We present the clinical data of 16 patients with renal granulomas, from a total group of 157 patients with systemic vasculitis. Their renal functioning was not significantly different from the other 141 patients in whose renal biopsies renal granulomas were present. Furthermore, we present two practical definitions for the recognition of renal granulomas in the kidney biopsy, and we show a number of examples of their various histopathological shapes.

Congenital glomerulopathies are rare but very severe diseases from the clinical point of view. Their origin is either located in the kidney itself or outside the kidneys. The exact differential diagnosis is only possible taking into consideration other organ systems. A histological certification is mostly inevitable. The prognosis of congenital glomerulopathies is usually bad due to the development of chronic renal failure in most cases. Therapeutic aspects are limited to a small number of specific forms. Recurrences in a renal graft, however, are usually not to be expected.

To assess the epidemiology of habitual use of analgesics in South-West Germany (i) urine specimens of employees of a factory, of patients seen by a general practitioner (GP) and of patients attending a renal clinic were examined for paracetamol; (ii) mucosa of the left renal pelvis was examined for the presence of capillary sclerosis as an index of habitual use of phenacetin or paracetamol in 258 consecutive autopsies; (iii) in a regional renal clinic, the frequency of analgesic nephropathy was determined amongst outpatients and amongst patients on hemodialysis. Paracetamol was found in the urine of 4.1% of factory employees, in 3.5% of patients seen by a GP and in 2% of patients seen in the renal clinic. Capillary sclerosis was found in only one of 258 autopsies, in a patient dialysed for analgesic nephropathy. During the past two years, analgesic nephropathy was diagnosed in 3% of all patients seen for nephrological examination. Analgesic nephropathy was the cause of terminal renal failure in 15 of 166 patients (9.4%) on dialysis. The present study documents that habitual use of paracetamol-type analgesics continues in the general population despite the ban of phenacetin.

Epidermolysis bullosa dystrophica Hallopeau-Siemens (EBDH) is one of the most severe inherited epidermolyses, a group of mechanobullous dermatological disorders. We observed two patients presenting with a severely multilating type of EBDH who developed biopsy-proven renal disease, which substantially altered the evolution and pathogenesis of their disease. In a boy, chronic postinfectious glomerulonephritis developed, most probably due to recurring superinfections of bullous skin lesions. He also experienced acute oliguric renal failure due to severe diarrhea during exacerbation of EBDH. A female patient developed a nephrotic syndrome due to secondary amyloidosis. Hypoalbuminemia caused further fluid losses through bullous skin lesions, aggravating intravascular hypovolemia and leading to rapid renal failure secondary to bilateral renal vein thrombosis. The study shows that, although rare, renal complications may alter the natural course of EBDH.

Kidney biopsy specimens of three patients with a special form of hypoplasia, the oligomeganephronic hypoplasia (Oligomeganephronie) were studied with light- and electron-microscopy as well as morphometric methods. The morphometric measurements demonstrated that there were no quantitative differences of the glomerular components between normal and oligomeganephronic glomeruli of patients of the same age. All of the structures measured--glomerular capillary surface, glomerular volume, volume of the glomerular capillary lumina and volume of Bowman's capsular space--were increased about 5.4 times. The volume of the proximal and distal tubules per mum tubular length in oligomeganephronic patients was disproportionally increased. The total number of glomeruli was more diminuished than mentionned in the literature until this time. The secondary glomerular sclerosis, initially focal, was progressive and supposed to be caused by "chronic overwork".

MHC class I and II molecules serve as restriction elements for the presentation of antigen-specific T cell reactions and may be implicated in the process of cellular transformation. We have analysed the expression of MHC class I and II antigens including the associated invariant gamma-chain in 100 consecutive renal biopsies by a sensitive immunoperoxidase method using monoclonal antibodies against HLA-ABC, HLA-DR, HLA-DQ, HLA-DP and the invariant gamma-chain (Ii). HLA-ABC was expressed by almost all parenchymal cells except for podocytes. Staining for HLA-DR was found consistently in glomerular and interstitial capillary endothelial cells, in "dendritic" (LCA positive) and most infiltrating interstitial cells but not in mesangial and most extracapillary cells. Similar but weaker positivity was observed for HLA-DQ and -DP. HLA-DR positive infiltrating mononuclear cells in glomeruli were noted in acute glomerulonephritis (GN) and Lupus GN associated with enhanced staining of endothelial cells. In addition, HLA-DR was uniformly or focally expressed by predominantly proximal tubules in 80% of biopsies, especially IgA-GN, focal glomerulosclerosis, acute GN but also in 54% of cases with minimal change nephrosis. HLA-DP and -DQ were only positive in a limited number of HLA-DR positive tubules. The expression of the invariant gamma-chain was comparable with the reactivity for HLA-DR. In addition, all HLA-DR-positive tubules expressed the invariant gamma-chain. Subtyping of T cells in biopsies with DR-positive tubules and interstitial infiltrates (n = 20) showed a predominance of CD 4 positive cells in the majority of cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Mesangial deposition of IgA (MCA) is a very rare finding in minimal change disease and has previously been considered a pure coincidence. In the US and Europe only anecdotal case reports exist. To date, there has been no consensus on nomenclature and categorization of this entity. We describe 2 cases of MCA with analogue histological findings but relevant differences in clinical presentation, and we discuss the clinical implications of mesangial IgA deposition in minimal change nephrotic syndrome. Patients: A 47 year-old fe male was admitted to hospital with nephrotic syndrome, microscopic hematuria, arterial hypertension and slight impairment of renal function 3 weeks after an unspecific upper air way infection. A 42-year-old male presented with nephrotic syndrome, microscopic hematuria, normotension and normal renal function. Both of the nephrotic syndromes were steroid-responsive and steroid-dependent. Findings: The clinical presentation of the male patient was consistent with the features of minimal change glomerulopathy, whereas the female patient combined signs of minimal change disease and IgA nephropathy. Light microscopy revealed mesangial IgA immune deposits and slight mesangial hypercellularity. Electron microscopic studies of MCA patients disclose diffuse effacement of glomerular foot processes. Conclusion: Our cases and a review of the literature indicate that the histological diagnosis of MCA may comprise different pathogenetic entities. From the clinical point of view, MCA has to be regarded as a minimal change nephrotic syndrome with symptomatic or asymptomatic mesangial IgA deposition. IgA deposition constitutes a risk factor for impairment of renal function and indicates a frequently relapsing course. [ABSTRACT FROM AUTHOR]

We studied the long-term outcome of 64 children with biopsy-proven Sch6nlein-Henoch purpura (SHP) nephritis over 1-23 years of follow-up. Overall renal survival 10 years after onset was 73%. Multivariate logistic regression analysis identified initial renal insufficiency (P=0.004), nephrotic syndrome (P=0.037), and the severity of histological alterations, as defined by the proportion of glomerular crescents (P=0.051), as significant independent predictors of progressive renal failure. Four patients followed for more than 19 years showed glomerular damage after transient recovery. Eight children with crescentic nephritis associated with a rapidly progressive course and/or persistent nephrotic syndrome were treated by at least seven sessions of plasma exchange (PE) within 16 weeks of onset of purpura. During treatment serum creatinine levels dropped in each patient from a mean of 2.3 to 1.1 mg/dl, followed by a rebound increase. Repeated courses of PE in 5 patients produced comparable responses. Four patients undergoing PE reached end-stage renal disease at 1.2.-3.7 years after onset, whilst 3 finally were in preterminal renal failure (creatinine 3.2-6.1 mg/dl after 7-13.5 years), and 1 patient reached a normal glomerular filtration rate. Our experience suggests that initial renal insufficiency is the best single predictor of the further clinical course in children with SHP nephritis. Early PE appears to delay the progression in some patients with severe, rapidly progressive forms of the disease. [ABSTRACT FROM AUTHOR]

The deposition of complement in the kidney mesangium is a constant finding associated with renal injury in IgA nephropathy, even though IgA does not bind complement. We have previously reported that complement gene expression in the kidney increases concurrently with the progression of immune complex disease in murine lupus nephritis. We have now studied the expression of C3, C4, factor B and HLA-DRα mRNA by in situ hybridization in renal biopsy specimens of patients with IgA nephropathy and compared these findings to those in patients with other immune-mediated diseases of the kidney, hereditary nephritis and normal kidney. In IgA nephropathy, C3 and factor B mRNA were expressed in the renal tubular epithelial cells, while no expression of either C3 or factor B mRNA was apparent in the glomerulus. Specimens from patients with other immune-mediated forms of chronic glomerulonephritis also showed a similar pattern of expression of C3 and factor B mRNA only in the tubules, but not in the glomerules. However, C3 and factor B mRNA were not found in normal kidney tissue or biopsy specimens from patients with hereditary nephritis. C4 mRNA was expressed in the tubular epithelial cells in all specimens examined, indicating that C4 mRNA is constitutively expressed in the human kidney. In IgA nephropathy HLA-DRα mRNA was observed in the interstitium, but not the tubules or glomerular cells. In contrast, HLA-DRα mRNA was present in the glomerulus and scattered in the interstitium in other immune-mediated kidney diseases. There was no expression of HLA-DRα mRNA in hereditary nephritis or normal kidney. Our findings, which reflect the immunopathogenic events in vivo, provide new insights as to the interpretation of the molecular immunology of this immune complex disease. [ABSTRACT FROM AUTHOR]

Micro-vascular and renal complications in diabetic patients are a considerable clinical challenge. In a previous study, we found a significant decrease in vascular endothelial growth factor A (VEGF-A) mRNA levels in glomeruli from patients with diabetic nephropathy (DN). We now set out to investigate the relationship between reduced VEGF-A and connective tissue growth factor (CTGF) expression levels, the number of podocytes, and the extent of interstitial fibrosis. Laser capture microdissection was applied to obtain glomerular RNA from 28 patients with DN and 22 controls. mRNA levels of VEGF-A, CTGF, nephrin, podocin, and Wilms tumor1 (WT1) were measured using real-time polymerase chain reaction. Protein expression was evaluated using immuno-stainings for VEGF-A and CTGF, as well as markers for podocytes (WT1) and endothelial cells (CD31). We found a significant decrease in glomerular mRNA levels for VEGF-A (2.5 times), CTGF (1.6), nephrin (2.8), podocin (3.3), and WT1 (1.7) in patients with DN. There was a significant correlation between expression of podocyte markers and VEGF-A mRNA levels, and an inverse correlation between podocin message and the extent of interstitial fibrosis. CD31-positive area was significantly decreased (3.2 times) in patients with DN. Reduction of angiogenic factors correlated with the extent of interstitial fibrosis. This downregulation was related to a reduction of podocytes in DN. The results may suggest that downregulation of VEGF-A and CTGF in DN is a result of podocyte loss.Kidney International (2007) 71, 637–645. doi:10.1038/sj.ki.5002101; published online 31 January 2007 [ABSTRACT FROM AUTHOR]