Abstract
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.
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.
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.
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.
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.
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•A population pharmacokinetic model was constructed for rituximab based on real data.•Rituximab elimination is faster in lupus nephritis, FSGS and MN than in AAV and MCD.•Proteinuria and the formation of ADA significantly enhance rituximab elimination.•The clearance (CL) of rituximab decreases with the treatment duration.•The dosing interval must be shortened for selected patients to overcome fast CL.
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.
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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.
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.
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).
This single-centre retrospective cohort study supports the beneficial role of the administration of corticosteroid therapy in the management of ATIN.
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 (
51
Cr-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 m
2
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.
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).
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.
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.
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.
Background. Fabry disease (FD) is a genetic disorder characterized by accumulation of trihexosylceramide in lysosomes of various tissues leading to multiorgan manifestations, including progressive ...renal disease. Previous screening studies have shown that a non-neglectable proportion of haemodialysis(HD) patients have unsuspected FD. An extensive FD screening study, the largest to date, has been conducted in HD patients in Czech Republic. We aimed to uncover previously undiagnosed FD patients, to enable them to benefit from cause-specific therapeutic intervention with enzyme replacement therapy (ERT). Methods. Large-scale screening was executed using a convenient automated enzymatic (α-galactosidose A, α-Gal A) dried blood spot on filter paper fluorescence method. Results. In total, 3370 (45.1% males, 54.9% females) out of 4058 HD patients (83%) in Czech Republic participated in this blood spot screening (BSS) study. Abnormal low fluorescence readings were obtained in 117 patients (3.5%). Subsequent determination of plasma α-Gal A activity identified four males and three females with deficient plasma enzyme activity. Determination of α-Gal A activity in peripheral blood leucocytes and confirmatory molecular analysis resulted in four newly diagnosed Fabry males and one female. Subsequent family screening identified 10 family members with genotypically proven FD. Based on these screening results, ERT could be offered to five male FD patients. Conclusions. BSS represents a promising screening tool that has proven to be convenient and effective in uncovering unrecognized FD patients among the chronic HD population in Czech Republic.
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
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
, MCPggaac haplotype of the
gene, and the risk haplotype
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.
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.
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.
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.
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.
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