Clinical Features, Outcomes, and Response to Corticosteroid Treatment of Acute Tubulointerstitial Nephritis: A Single-Centre Retrospective Cohort Study in the Czech Republic.

INTRODUCTION: Acute tubulointerstitial nephritis (ATIN) is a well-recognized cause of acute kidney injury (AKI) due to the tubulointerstitial inflammation. The aim of this study was to explore the clinical features, outcomes, and responses to corticosteroid treatment in patients with ATIN. METHODS: Patients with biopsy-proven ATIN, who were diagnosed between 1994 and 2016 at the Department of Nephrology, Charles University, First Faculty of Medicine, and General University Hospital in Prague, were included in the study. Patient demographics, the aetiological and clinical features, the treatment given, and the outcome at 1 year of follow-up were extracted from patient records. RESULTS: A total of 103 ATIN patients were analysed, of which 68 had been treated with corticosteroids. There was no significant difference in the median serum creatinine 280 (169-569) µmol/L in the conservatively managed group versus 374 (249-558) µmol/L in the corticosteroid-treated group, p = 0.18, and dependence on dialysis treatment at baseline at the time of biopsy (10.3 vs. 8.6%). During the 1 year of follow-up, those ATIN patients who had been treated with corticosteroids did better and showed greater improvement in kidney function, determined as serum creatinine difference from baseline and from 1 month over 1-year period (p = 0.001). CONCLUSIONS: This single-centre retrospective cohort study supports the beneficial role of the administration of corticosteroid therapy in the management of ATIN.

Renal impairment in monoclonal gammopathies and multiple myeloma.

The incidence of monoclonal gammopathy (MG) increases with age. In individuals over 80 years of age, we can diagnose the presence of monoclonal immunoglobulin (MIg) in up to 10 % of cases. Not only malignant diseases such as multiple myeloma (MM), but also benign forms such as MGUS (monoclonal gammopathy of undetermined significance) can lead to renal involvement. The light chains of immunoglobulins (LC) are the most damaging to the kidneys, as they are freely filtered into the urine due to their molecular weight. Detection of MIg relies mainly on a combination of immunofixation electrophoresis of serum (IELFO) and urine and determination of free light chains (FLC) of kappa and lambda and their ratio (κ/λ) in serum. The combination of these tests will detect the presence of MIg with 99 % sensitivity. Renal damage in MG may be caused by direct deposition of MIg in the glomeruli (e.g. AL amyloidosis, LC deposition disease) or tubules (in the distal tubule as a myeloma kidney or in the proximal tubule as Fanconi syndrome or proximal tubulopathy). Typical urinary findings in these diseases are moderate or severe proteinuria or nephrotic syndrome. Acute kidney injury (AKI) can be expected especially when serum FLC is >500 mg/l. Renal biopsy is crucial to establish an accurate diagnosis and thus initiate the correct treatment. Treatment of these types of renal damage involves the same treatment regimens used in the treatment of MM, including proteasome inhibitors or daratumumab.

A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.

Amyloid A amyloidosis is a serious clinical condition resulting from the systemic deposition of amyloid A originating from serum amyloid A proteins with the kidneys being the most commonly and earliest affected organ. Previously described amyloid A amyloidosis is linked to increased production and deposition of serum amyloid A proteins secondary to inflammatory conditions arising from infectious, metabolic, or genetic causes. Here we describe a family with primary amyloid A amyloidosis due to a chr11:18287683 T>C (human genome version19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype. This condition leads to a doubling of the basal SAA1 promoter activity and sustained elevation of serum amyloid A levels that segregated in an autosomal dominant pattern in 12 genetically affected and in none of six genetically unaffected relatives, yielding a statistically significant logarithm of odds (LOD) score over 5. Affected individuals developed proteinuria, chronic kidney disease and systemic deposition of amyloid composed specifically of the SAA1.1 isoform. Tocilizumab (a monoclonal antibody against the interleukin-6 receptor) had a beneficial effect when prescribed early in the disease course. Idiopathic forms represent a significant and increasing proportion (15-20%) of all diagnosed cases of amyloid A amyloidosis. Thus, genetic screening of the SAA1 promoter should be pursued in individuals with amyloid A amyloidosis and no systemic inflammation, especially if there is a positive family history.

New developments in anaemia treatment - erythropoietin versus prolyl hydroxylase inhibitors?

Anaemia is a very common complication of chronic kidney disease (CKD) and renal failure. The view of the treatment of anaemia has changed considerably since the introduction of ESAs (erythropoiesis-stimulating agents) into clinical practice, and the safety of this treatment is now prioritised over complete normalisation of haemoglobin (Hb) values. Iron administration is the mainstay of treatment in this group of patients, with intravenous administration proving to be both more effective and safer in both predialysis and dialysis patients. In addition to the long-used ESAs, a number of new agents developed to favourably influence erythropoiesis have recently been tested for the correction of anaemia. Among those with the greatest potential are the HIF-stabilizers (roxadustat, molidustat, vadadustat and daprodustat), which act through stimulation of erythropoiesis genes and thus represent a novel mechanism of action in the treatment of anaemia. In phase 3 clinical trials, these agents have shown the same efficacy in increasing Hb levels as ESAs, but much emphasis has recently been placed on their safety profile. They are orally administered agents and some of them are already approved and used in clinical practice. The first of these, roxadustat, is currently reimbursed also in the Czech Republic. Other molecules affecting anaemia, such as sotatercept, have also been confirmed to be effective in phase 1 and 2 clinical trials and are awaiting results from larger randomised trials.

Expert opinion on the cooperation of diabetologists and internists with nephrologists in the care of patients with chronic kidney diseases.

Chronic kidney disease (CKD) affects 10% of the population of developed countries and significantly affects the population health. In addition to the well-known renoprotection tools slowing down the progression of CKD, SGLT2 inhibitors have been newly introduced into clinical practice based on the results of extensive studies, both in diabetics and non-diabetics. This expert opinion discusses the classification of CKD, current renoprotection options, and the recent role of SGLT2 inhibitors in the care of patients with CKD.

Renal failure in multiple myeloma and its treatment.

Renal failure is a serious complication of multiple myeloma, and up to 50% of patients with this most frequent haematological malignancy may develop some form of renal impairment.  The aetiology of renal damage is multifactorial, but increased production of free light chains that are filtered into the urine is crucial for the development of renal failure and could be associated with distal tubule involvement (myeloma kidney, light chain cast nephropathy) or with fully developed Fanconi syndrome in proximal tubule damage (proximal tubulopathy, light chain proximal tubulopathy). Glomerular damage most often manifests as AL amyloidosis or light chain deposition disease; both cause severe nephrotic syndrome. Early and adequate chemotherapy in association with symptomatic treatment can lead to rapid reduction of serum light chain concentration which is necessary to prevent development of renal failure. At present, effective therapeutic procedures can be used for this purpose, where especially a triple combination of treatment containing one of the proteasome inhibitors (bortezomib, carfilzomib or ixazomib) is able to elicit a haematological response within a few days. If there is a good haematological response to treatment, up to 50% of patients with renal failure will restore their renal function. Renal function repair can be accelerated by removing light chains from serum by dialysis with high-cutoff membrane (HCO-HD). Using this procedure can increase the chance of dialysis independence in more than 60% of patients with renal failure.  Data from previously published studies on HCO-HD (MYRE or EuLITE study) have not yielded as optimistic results as originally expected, however, HCO-HD could be beneficial for some subgroup of patients with renal failure in myeloma kidney. Despite the fact that overall prognosis and survival of patients with multiple myeloma have dramatically improved, the condition with renal failure in these patients remains serious.

AL amyloidosis: advances in diagnostics and treatment.

AL amyloidosis (light chain; previously also called primary amyloidosis) is a systemic disease characterized by an amyloid deposition process affecting many organs, and which still has unsatisfactory survival of patients. The monoclonal light chains kappa (κ) or lambda (λ) or their fragments form the fibrils that deposit and accumulate in different tissues. Renal involvement is very frequent in AL amyloidosis and can lead to the development of nephrotic syndrome followed by renal failure in some cases. AL amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment, the importance of an early diagnosis of amyloidosis and correct assessment of its type is high. Histologic confirmation is based on Congo red detection of amyloid deposits in tissues but AL amyloidosis must also be distinguished from other systemic forms of amyloidoses with renal involvement, such as AA amyloidosis, amyloidosis with heavy chain deposition, fibrinogen Aα or ALECT2 (leukocyte chemotactic factor 2) deposition. Immunofluorescence (IF) plays a key role here. IF on formalin-fixed paraffin-embedded tissue after protease digestion, immunohistochemistry or laser microdissection with mass spectrometry should complete the diagnosis in unclear cases. Standard treatment with melphalan and prednisolone or with cyclophosphamide and dexamethasone has been replaced with newer drugs used for the treatment of multiple myeloma-bortezomib, carfilzomib and ixazomib or thalidomide, lenalidomide and pomalidomide. High-dose melphalan supported by autologous stem cell transplantation remains the therapeutic option for patients with low-risk status. These new treatment options prolong survival from months to years and improve the prognosis in a majority of patients.

Assessment of renal function before contrast media injection: right decisions based on inaccurate estimates.

OBJECTIVES: Information on renal function required before specified radiological examinations with contrast agents is usually obtained through prediction equations using serum creatinine and anthropometric data. The aim of our study was to demonstrate discrepancy between poor prediction and good diagnostic accuracy of glomerular filtration rate (GFR) estimated by prediction equations. METHODS: In 50 patients, reference GFR was measured as plasma clearance of 51-chromium labeled ethylene-diamine-tetraacetic-acid (51Cr-EDTA) and compared with GFR assayed by creatinine clearance (CC) and estimated by Cockcroft-Gault prediction equation (CG). For comparisons, CC and CG were considered as continuous, categorical, and binary variables. Accuracy of the reference GFR prediction was expressed in terms of prediction errors and diagnostic accuracy indices. RESULTS: As continuous variable, CG estimated individual values of GFR with large prediction error exceeding that of CC. As categorical variable, it classified the patient stage of chronic kidney disease (CKD) with medium diagnostic accuracy of 74% (CKD 3) and 62% (CKD 4). As binary variable, CG classified individual patient's GFR below 30 and 60 ml/min/1.73 m2 with good diagnostic accuracy of 80 and 94%, respectively. Performance of other prediction equations did not significantly differ from CG. CONCLUSIONS: Despite large variance and poor prediction accuracy of individual GFR estimates, most of them correctly classified individual patient's GFR below specified level. Results of prediction equations thus should be used and reported exclusively as binary variables, while numerical values of GFR, if required, should be measured by more accurate radionuclide or laboratory methods. KEY POINTS: • Radiological guidelines on contrast media require estimation of glomerular filtration rate to assess kidney function before specified contrast examinations. • Estimated glomerular filtration rate is obtained through prediction equations using serum creatinine and anthropometric data as predictors. • While numerical estimates of glomerular filtration rate are inaccurate (their prediction accuracy is poor), diagnostic accuracy of binary estimates (ability to classify patient's glomerular filtration rate below or above a specified level) is very good.

[Theralite and multiple myeloma]. / Theralite a mnohocetný myelom.

Multiple myeloma associated with an increased FLC production causes renal failure (cast nephropathy) requiring dialysis. Theralite is a dialyser with a high cut-off membrane (HCO) - with large size pores that allow permeability for substances of molecular masses up to 45 kDa. The FLC concentrations over hemodialysis will significantly decrease and if hematological treatment is also effective, the FLC production will significantly fall as well. The aim of this comprehensive therapy is to improve the renal functions to such an extent that a substantial removal of FLC (70-90 %) is reached in patients and even interruption of dialysis therapy (50-75 %). The number of HD with this membrane rather varies in individual patients according to the literature (e.g. an average of 12 HDs/per 1 patient - 3-45). Our cohort comprised 17 patients aged 38-71 years, with 9 HDs per 1 patient, 10 patients (59 %) stopped the dialysis therapy and 7 remained on the dialysis programme. FLC removal reached 87 % in the whole cohort after the completed HDs with Theralite, but it specifically reached 93 % in the patients without further dialysis therapy, as opposed to 75 % in those who continued to undergo HD. No patient died when receiving HD with Theralite, in 4 complications occurred without causing interruption of the therapy. We assume that monitoring FLC concentrations before each dialysis may be of prognostic significance for patients including the length of treatment with an HCO membrane. Close cooperation with a hematologist is necessary.Key words: cast nephropathy - FLC - HCO membrane - multiple myeloma - kidney failure - Theralite.

[Gitelman´s syndrome as common cause of hypokalemia and hypomagnesemia]. / Gitelmanuv syndrom jako castá prícina hypokalemie a hypomagnezemie.

The Gitelman syndrome (GS) is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis and presence of hypocalciuria and hypomagnesemia. It is one of the most common congenital "salt-wasting" tubulo-pathies, where the impairment of function of the Na+-Cl- cotransporter (NCCT) in the distal convoluted tubule is primary and hypokalemia secondary. Hypomagnesemia is caused by the impairment of magnesium reabsorption through TRPM6 channel which is located just by NCCT. Clinically, patients suffer from fatigue and hypotension due to loss of salt and water and also have cramps and tetany. In some patients chondrocalcinosis can be identified which leads to protracted pain and repeated aseptic inflammations in the joints. The course of the disease, though, is typically benign, and it rarely leads to structural changes in the kidneys or renal impairment. In the period of 2004-2006 we commenced examination of patients with suspected GS based on clinical and laboratory findings within a grant project in the Czech Republic, and in the following years this methodology was introduced to the common laboratory practice. By the year 2011 we had identified 7 different causal mutations in the gene SLC12A3 (4 of them new) among the Czech population, which is responsible for the origin of this disease. The majority of patients, whose clinical findings indicated the presence of GS, had the mutation actually detected, specifically in heterozygous form; 4 individuals were then homozygous. Most of the identified mutations were missense mutations and the most common type found among the Czech population was the change 1315 G>A within the geneSLC12A3, which causes impairment of glycosylation of the NCCT transporter. Further a great number of single-nucleotide polymorphisms were found that may be involved in clinical manifestation of the disease.Key words: gene mutation - gene sequence - Gitelman´s syndrome - NCC channel - PCR.

IgA nephropathy in Czech patients--are we able reliably predict the outcome?

BACKGROUND/AIMS: The aim of our study was to retrospectively analyse data of 520 Czech patients with IgA nephropathy (IgAN) and to specify the risk factors affecting renal survival of IgAN patients. METHODS: Cox proportional hazards regression model was used to evaluate the effects of different variables on renal survival during a median follow up of six years. McNemar´s test was used to analyse the progression of renal function according to Bartosik´s formula. RESULTS: In our retrospective analysis of 520 Czech IgAN patients Cox proportional hazards regression model with five variables [hypertension, sex, GFR, proteinuria, age] was used. Significant regression coefficient was found for GFR, hypertension and proteinuria. Using stepwise algorithm GFR (OR = 3.09), hypertension (OR = 2.09) and proteinuria (OR = 1.97) were found as the most important factors for renal survival in our group of IgAN patients. Among patients with CKD 3 we found significantly better renal survival in patients with proteinuria < 1g/day compared to patients with higher proteinuria. We did not find the significant difference between predicted progression of renal function due to Bartosik´s formula and real progression of renal parametres assessed by GFR at the end of the follow up in our group of IgAN patients. CONCLUSION: Our retrospective study of 520 Czech IgAN patients confirmed GFR, hypertension and proteinuria as the most important factors affecting the prognosis of IgAN patients. We validated Toronto Bartosik´s formula to predict prognosis of IgAN patients.

A novel dosing approach for rituximab in glomerular diseases based on a population pharmacokinetic analysis.

OBJECTIVES: Rituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug. METHODS: We compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients' characteristics, rituximab levels and anti-rituximab antibodies. RESULTS: The analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria. CONCLUSION: In order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases.

The coincidence of IgA nephropathy and Fabry disease.

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis, which may also coexist with other diseases. We present two patients with an unusual coincidence of IgAN and Fabry disease (FD). CASE PRESENTATION: A 26 year-old man underwent a renal biopsy in February 2001. Histopathology showed very advanced IgAN and vascular changes as a result of hypertension. Because of his progressive renal insufficiency the patient began hemodialysis in August 2001. By means of the blood spot test screening method the diagnosis of FD was suspected. Low activity of alpha-galactosidase A in the patient's plasma and leukocytes and DNA analysis confirmed the diagnosis of FD. Enzyme replacement therapy started in July 2004. Then the patient underwent kidney transplantation in November 2005. Currently, his actual serum creatinine level is 250 µmol/l. Other organ damages included hypertrophic cardiomyopathy, neuropathic pain and febrile crisis. After enzyme replacement therapy, myocardial hypertrophy has stabilized and other symptoms have disappeared. No further progression of the disease has been noted.The other patient, a 30 year-old woman, suffered from long-term hematuria with a good renal function. Recently, proteinuria (2.6 g/day) appeared and a renal biopsy was performed. Histopathology showed IgAN with remarkably enlarged podocytes. A combination of IgAN and a high suspicion of FD was diagnosed. Electron microscopy revealed dense deposits in paramesangial areas typical for IgAN and podocytes with inclusive zebra bodies and myelin figures characteristic of FD. FD was confirmed by the decreased alpha-galactosidase A activity in plasma and leukocytes and by DNA and RNA analysis. Enzyme replacement therapy and family screening were initiated. CONCLUSIONS: Our results emphasize the role of complexity in the process of diagnostic evaluation of kidney biopsy samples. Electron microscopy represents an integral part of histopathology, and genetic analysis plays a more and more important role in the final diagnosis, which is followed by causal treatment.

Biomarkers of fibrosis, kidney tissue injury and inflammation may predict severity and outcome of renal ANCA - associated vasculitis.

Background: Activity and chronicity of kidney involvement in ANCA-associated vasculitis (AAV) can be currently reliably evaluated only by kidney biopsy. In this study, we measured a panel of serum and urinary biomarkers collected at the time of kidney biopsy and hypothesized that they could reflect specific histopathological parameters in the biopsy and help to predict prognosis. Methods: We examined a cohort of 45 patients with AAV and 10 healthy controls. Biomarker levels (DKK-3, CD163, EGF, PRO-C6 and C3M) were measured in this study by ELISA. Biopsies were scored with a scoring system for AAV (focal x crescentic x sclerotic x mixed class) and interstitial fibrosis was quantified. Results: Levels of urinary DKK-3, CD163, EGF, PRO-C6 and C3M significantly differed among biopsy classes in AAV, with urinary DKK-3 and PRO-C6 levels being highest in the sclerotic class and lowest in the focal class, urinary CD163 levels highest in the crescentic class and urinary C3M levels highest in the focal class. Moreover, the urinary biomarkers were able to discriminate focal biopsy class from the other classes. Urinary DKK-3, EGF, PRO-C6 and C3M levels measured at the time of biopsy were also significantly related to the extent of fibrosis and to the final kidney function at the end of follow-up. Conclusions: This small pilot study suggests that selected urinary biomarkers of fibrosis and inflammation may reflect changes in the kidney biopsy and be prognostic of kidney outcome in patients with AAV.

The retrospective analysis of 343 Czech patients with IgA nephropathy--one centre experience.

BACKGROUND: The aim of our study was to retrospectively analyse the clinical data and the histological findings of 343 patients (pts) followed up with IgA nephropathy (IgAN) in our department of nephrology. We have assessed the main demographic, clinical and histological data, and the medical treatment of IgAN pts. METHODS: Multivariate analysis was used to evaluate the effect of different variables on ≥50% increase of plasma creatinine level from baseline during a median follow-up of 4 years. RESULTS: In our group of IgAN pts, the male gender (68%) predominated over female gender (32%). At the time of renal biopsy, the median age of IgAN pts was 32.3 (18-90) years, the median level of serum creatinine was 119 µmol/L and the median level of proteinuria was 1.8 g/day. Most of the pts were found to have arterial hypertension (56.7%). The majority of the pts with arterial hypertension were treated with inhibitors of angiotensin-converting enzyme (80.4%) and the remaining pts (42.6%) were treated with angiotensin II receptor blockers. Fifty per cent of the pts (170 pts) were treated of corticosteroids, 21% of the pts (71 pts) used a combined immunosuppressive treatment of corticosteroids and cyclophosphamide, 8% of the pts (27 pts) took azathioprine, 1.5% of the pts (5 pts) took cyclosporine and 1.5% of the pts (5 pts) were given mycophenolate mofetil. Hypertension at presentation, fibrointimal proliferation of arterial vessels, interstitial fibrosis and interstitial inflammation were shown to be associated with ≥50% increase of plasma creatinine level from baseline in univariate analysis (P<0.05 for hypertension and fibrointimal proliferation; P<0.01 for interstitial fibrosis and inflammation). Using stepwise logistic regression presenting proteinuria>2 g/day [odds ratio (OR)=2.24, P<0.01], tubular atrophy (OR=4.97, P<0.01) and damage of tubular epithelium (OR=1.78, P<0.05) were found as risk factors for ≥50% increase of plasma creatinine level from baseline. CONCLUSION: Our retrospective analysis found valuable information not only about the clinical, laboratory and histological findings in IgAN pts but also information about the risk factors influencing the progression of renal insufficiency.

Atypical hemolytic uremic syndrome triggered by mRNA vaccination against SARS-CoV-2: Case report.

Atypical hemolytic uremic syndrome (aHUS), also called complement-mediated hemolytic uremic syndrome (CM-HUS), is a rare disease caused by dysregulation in the alternative complement activation pathway. It is a life-threatening condition causing ischemia of a number of organs, and it typically causes acute kidney injury. This disorder may be triggered by various factors including viral or bacterial infections, pregnancy, surgery, and injuries. In about 60% of cases, the genetic origin of the disease can be identified-commonly mutations affecting complementary factor H and MCP protein. Eculizumab, a monoclonal antibody to the C5 component of the complement, represents the current effective treatment.We describe a case of a young woman with a previous history of polyvalent allergies, who developed atypical hemolytic uremic syndrome after vaccination with mRNA vaccine against SARS-CoV-2. The disease manifested by scleral bleeding, acute renal insufficiency, anemia, and thrombocytopenia. The patient was treated with plasma exchanges without sufficient effect; remission occurred only after starting treatment with eculizumab. Genetic examination showed that the patient is a carrier of multiple inherited risk factors (a rare pathogenic variant in CFH, MCPggaac haplotype of the CD46 gene, and the risk haplotype CFH H3). The patient is currently in hematological remission with persistent mild renal insufficiency, continuing treatment with eculizumab/ravulizumab. By this case report, we meant to point out the need for careful monitoring of people after vaccination, as it may trigger immune-mediated diseases, especially in those with predisposing factors.

FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy.

Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis.

BACKGROUND: A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. METHODS: A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. RESULTS: High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2-which is not reliable because of the small number of cases-strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3-4 had worse renal survival than patients in Clusters 1-2. CONCLUSIONS: Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

Mycophenolate mofetil in low doses stabilizes and improves antineutrophil cytoplasmic antibody-associated vasculitis and lupus nephritis.

BACKGROUND: Clinical experience with mycophenolate mofetil (MMF) in glomerulonephritis still remains limited. METHODS: In order to assess the experience of one center with the efficacy and tolerability of MMF in patients with glomerulonephritis, we performed a retrospective 6-year analysis of 68 patients treated by MMF for glomerular disease, mainly anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV: n=34) and systemic lupus erythematosus and lupus nephritis (SLE: n=24). Indications were maintenance treatment in 40% of patients, induction treatment in patients not tolerating cyclophosphamide in 27%, and disease relapse in 33%. Mean treatment duration was 11.5 months. RESULTS: Efficacy endpoints were serum creatinine, urinary protein excretion, and steroid dose. In AAV patients, MMF was associated with significant improvement in 18%, partial improvement in 26%, stabilization in 29%, and disease progression in 12%; adverse event dropouts totalled 15%. In SLE, the respective figures were 30, 22, 9, and 22%, with 17% adverse event dropouts. The most frequent side effects were gastrointestinal events (n=7) and infections (n=3). None was life-threatening and there were no deaths. CONCLUSIONS: MMF, in the relatively low doses used, was safe and effective, stabilizing or improving AAV in 73% of patients and SLE in 61%. Further prospective randomized controlled trials with MMF in renal vasculitis and lupus nephritis are clearly warranted.

Prevalence and risk of hypertension in renal disease--data from the Czech Registry of Renal Biopsies.

BACKGROUND/AIMS: We intended to compare the risk and prevalence of hypertension in patients undergoing renal biopsy with those of the general population and to investigate the possible effects of various independent factors (age, sex and degree of renal insufficiency) on the prevalence of hypertension. METHODS: Data obtained within the Czech Registry of Renal Biopsies over an 8-year period (1995-2002) were statistically evaluated and compared with those of the general population obtained within the Post-MONICA Study conducted in 2000/2001. RESULTS: Hypertension was present in 1,839 out of a total of 3,601 renal patients (51.1%). The risk of hypertension in the patients with renal disease was increased in all age groups compared with the general population (OR = 1.3-5.3). The prevalence of hypertension increased significantly with age, serum creatinine and proteinuria (p < 0.001). Male sex was identified as an independent risk factor for the presence of hypertension (p < 0.01). Sex, age and glomerular filtration rate were shown to be more important determinants of the risk of hypertension than the underlying biopsy-proven diagnosis itself. CONCLUSION: Hypertension occurs as a common complication of renal disease, even in its early stages, and irrespective of the histological finding.