Effect of serum creatinine difference between the Jaffe and the enzymatic method on kidney disease detection and staging.

Background: Serum creatinine (SCr), mainly determined by the Jaffe or an enzymatic method, is the central marker to assess kidney function. Deviations between these two methods may affect the diagnosis and staging of acute kidney injury (AKI) and chronic kidney disease (CKD). Methods: The results of the first parallel SCr measurement (Jaffe and enzymatic method) of adult in- and outpatients in the same serum sample at the University Hospital Essen (Essen, Germany) between 2020-2022 were retrospectively evaluated. A Bland-Altman plot with 95% limits of agreement (LoAs) was used to assess the difference between the Jaffe and the enzymatic SCr (eSCr) method. We used the 2009 Chronic Kidney Disease Epidemiology Collaboration equation for determination of estimated glomerular filtration rate (eGFR) according to the Kidney Disease: Improving Global Outcomes guidelines. Results: A total of 41 144 parallel SCr measurements were evaluated. On average, Jaffe SCr was 0.07 mg/dl higher than eSCr (LoA -0.12; 0.25 mg/dl). In 19% of all cases there was a different CKD stage when comparing eGFR between both SCr methods, of which 98% resulted in a more severe CKD stage determined with Jaffe SCr. In 1.6% of all cases Jaffe SCr was ≥0.3 mg/dl higher than eSCr. Conclusion: The present study showed that methods of SCr measurement may affect both the diagnosis and staging of AKI and CKD. This must be taken into account when interpreting measurements of renal function in everyday clinical practice, but also when planning and comparing studies on renal diseases. One should therefore stay with one method for SCr measurement, preferably with the enzymatic method.

No evidence for hypogammaglobulinemia in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with ravulizumab.

INTRODUCTION: Ravulizumab (ALXN1210) is a long-lasting recycling IgG monoclonal antibody with an increased affinity for the neonatal Fc receptor (FcRn). The FcRn is essential for regulating IgG homeostasis. Saturation of the FcRn pathway is seen under high IgG doses as they compete with endogenous IgG to bind the FcRn by their Fc regions, resulting in enhanced IgG clearance. PATIENTS/METHODS: Between Jan 2016 and Jun 2019 (median observation time 21.6 months (6-37.7 months)) serum IgG concentrations and IgG1-4 subclasses were evaluated over a longitudinal course (post-hoc analysis) in 12 ravulizumab-treated adult patients with paroxysmal nocturnal hemoglobinuria (PNH) (58% (7/12) males, median age 50 years (yrs) (18-70 yrs)). All patients were enrolled in one of the three ravulizumab-PNH-related trials (201-, 301-, or 302-study) at the University Hospital Essen. RESULTS: Baseline IgG concentrations were documented in 11 out of the 12 patients prior to ravulizumab treatment (median IgG 9.9 g/L (5-13.5 g/L)). In two female patients a clinically not relevant hypogammaglobulinemia with an associated IgG1 or a combined IgG1/IgG2 deficiency prior to treatment was documented. The data were further stratified with regard to various treatment intervals as multiple analyses were obtained. Throughout observation time IgG concentrations remained within physiologic ranges with no evidence of a treatment-related IgG depletion (median IgG at study endpoint 10.1 g/L (6-13.4 g/L)). CONCLUSION: In ravulizumab-treated PNH patients, IgG and IgG subclass levels which are regulated by the FcRn remained unaffected. Therefore, no treatment associated hypogammaglobulinemia is to be feared under chronic ravulizumab therapy.

Undue Elevation of Procalcitonin in Pediatric Paracetamol Intoxication is Not Explained by Liver Cell Injury Alone.

INTRODUCTION AND AIM: Procalcitonin is widely used as a biomarker to distinguish bacterial infections from other etiologies of systemic inflammation. Little is known about its value in acute liver injury resulting from intoxication with paracetamol. MATERIAL AND METHODS: We performed a single-center retrospective analysis of the procalcitonin level, liver synthesis, liver cell damage and renal function of patients admitted with paracetamol-induced liver injury to a tertiary care children's hospital. Children with acute liver failure due to other reasons without a bacterial or fungal infection served as the control group. Twelve patients with acute paracetamol intoxication and acute liver injury were compared with 29 patients with acute liver failure. RESULTS: The procalcitonin levels were higher in children with paracetamol intoxication than in patients with acute liver failure without paracetamol intoxication (median 24.8 (0.01-55.57) ng/mL vs. 1.36 (0.1-44.18) ng/mL; p < 0.005), although their liver and kidney functions were better and the liver cell injury was similar in both groups. Outcome analysis showed a trend towards better survival without transplantation in patients with paracetamol intoxication (10/12 vs. 15/29). Within each group, procalcitonin was significantly correlated with alanine aminotransferase and aspartate aminotransferase but was not correlated with the International Normalized Ratio or paracetamol blood levels in the paracetamol group. In conclusion, paracetamol intoxication leads to a marked increase in procalcitonin serum levels, which are significantly higher than those seen in acute liver failure. CONCLUSION: The underlying mechanism is neither caused by infection nor fully explained by liver cell death alone and remains to be determined.

Prognostic significance of serum cystatin C in multiple myeloma.

Multiple myeloma (MM) is frequently complicated by renal insufficiency, which is associated with an unfavorable prognosis. Serum cystatin C is a new and accurate marker of glomerular filtration rate. Global gene expression analysis has revealed serum cystatin C as one of the most highly upregulated genes in MM. Recent data have shown serum cystatin C as an independent prognostic marker in MM. To further elucidate the prognostic significance of serum cystatin C, we investigated pretreatment serum cystatin C levels in 68 newly diagnosed patients homogeneously treated with high-dose melphalan followed by autologous stem cell transplantation. Median serum cystatin C level in MM patients was significantly higher than in the 66 healthy controls (1.07 vs. 0.74 mg/L [p = 0.002]). Median serum cystatin C levels significantly increased with higher International Staging System (ISS) stages (stage I 0.72 mg/L; stage II 0.89 mg/L; stage III 1.28 mg/L; p < 0.0001). Higher serum cystatin C was positively correlated with higher serum levels of creatinine (r = 0.84; p < 0.0001), ß2-microglobulin (r = 0.72; p < 0.0001), LDH (r = 0.43; p = 0.0003), white blood cell counts (r = 0.61; p < 0.0001) and calcium (r = 0.29; p = 0.016), and negatively correlated with lower serum albumin levels (r = 0.44; p < 0.0001) and hemoglobin levels (r = 0.31; p = 0.01). Using ROC analysis, patients with serum cystatin C levels ≥0.95 mg/L (n = 24) had a significantly shorter event-free survival (EFS) and overall survival (OS) than patients with serum cystatin C levels <0.95 mg/L (median EFS: 26 vs. 44 months, p < 0.0001; median OS: 54 vs. 68 months, p = 0.05). Moreover, the combination of serum cystatin C level and genomic aberrations further refined the prognostic information (EFS and OS) provided by either one of the factors. The level of serum cystatin C is not only a sensitive marker of renal function, but also reflects tumor burden and delivers prognostic information in MM.

Prevalence and progression of monoclonal gammopathy of undetermined significance and light-chain MGUS in Germany.

We determined the prevalence and progression rate of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS (LCMGUS) in Germany utilizing the biobank of the population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4,814 men and women aged 45-75 years. To detect monoclonal proteins, standard serum electrophoresis was combined with parallel screening immunofixation using pentavalent antisera. Additionally, free light chains (FLC) were measured in all samples. Definition of MGUS included M-protein concentration, laboratory results, and disease history. LCMGUS was defined as abnormal FLC ratio, increase in FLC causing the abnormal ratio, and lack of intact immunoglobulin. One hundred sixty-five MGUS cases were identified among 4,702 screened samples (prevalence 3.5%, 95% confidence interval (CI) 3.0-4.1; median age 63 years, range 47-75 years; 103 (62%) male; IgG 59%, IgA 17%, IgM 17%, biclonal 4.8%, kappa 56%, and lambda 44%). Five cases progressed (0.6%/year, 95% CI 0.2-1.4). An abnormal FLC ratio was detected in 220 samples. Thirty-nine of these showed intact immunoglobulin. Thirty-four of the remaining met LCMGUS criteria (prevalence 0.7%, 95% CI 0.5-1.0). None of the LCMGUS cases progressed. We demonstrate a MGUS prevalence of 3.5% and a LCMGUS prevalence of 0.7% in the general population aged 45-75 years in Germany using a sensitive screening approach.

Sensory neuropathy in patients with cryoglobulin negative hepatitis-C infection.

There is growing evidence that hepatitis-C virus (HCV) infection might cause peripheral neuropathy. We aimed to investigate the prevalence, clinical and electrophysiological features of sensory neuropathy in patients with cryoglobulin negative HCV infection. We studied 46 consecutive cryoglobulin negative HCV positive patients (24 of them with and 22 without neuropathic symptoms, NS) and compared to 28 age and gender matched controls. In all patients and controls, clinical neuropathy symptom (NSS) and neuropathy deficit scores (NDS) were assessed and standard nerve conduction velocity (SNCV) and pain related-evoked potentials (PREP) were recorded. Both, SNCV and PREP were abnormal in 13 NS positive patients (13/46, 28%). Abnormal PREP but normal SNCV were found in 5 (5/46, 11%) NS positive and in 2 NS negative patients (2/46, 4%). PREP abnormalities correlated positive with both clinical neuropathy scores (NSS r=0.62; p<0.001; NDS r=0.57; p<0.001), but not with the duration of the disease, current viral load, or the virus subtype. PREP abnormalities were more frequent (16/33, 48.5%) in HCV patients treated with interferon than in therapy naïve patients (4/13, 30.8%); the difference was, however, not significant. In our present study (1) all virus subtypes are capable of inducing neuropathy, (2) no differences were found between interferon therapy and treatment naive patients, (3) the prevalence of peripheral sensory neuropathy including small sensory fibers (20/46, 43.5%) is higher than previously reported and (4) we found that detection of HCV associated neuropathy depends on the evaluation method.

Serum cystatin C in mouse models: a reliable and precise marker for renal function and superior to serum creatinine.

BACKGROUND: Serum creatinine (SCR) and blood urea nitrogen (BUN) determine the glomerular filtration rate (GFR) improperly in acute renal failure. Serum cystatin C (CYS) has the potential to be a more precise marker for GFR. The aim of this study was to compare the sensitivity of SCR, BUN and CYS with respect to the detection of acute renal failure in mice. METHODS: In an ischaemia reperfusion (I/R) injury model, mice suffered 60-min left kidney ischaemia and right nephrectomy. In a nephrectomy model, mice were nephrectomized to a different extent: from unilateral (3/6Nx) to bilateral nephrectomy (BiNx). Blood samples were collected 2, 12 or 24 h post-op. RESULTS: SCR, BUN and CYS increased significantly in the I/R-model in comparison to sham mice and 3/6Nx mice at 12 and 24 h post-op (SCR P = 0.009; BUN P < 0.001 and CYS P < 0.004). There were no significant differences in all three markers between 3/6Nx and sham-operated mice. In graded nephrectomy, BUN and CYS showed already significantly the loss of kidney in 4/6Nx mice 12 h post-op [BUN (mg/dl): sham 26.4 +/- 3.5, 4/6Nx 52.3 +/- 13.4, P < 0.01; CYS (mg/l): sham 0.08 +/- 0.03, 4/6Nx 0.15 +/- 0.04, P < 0.01], whereas SCR was only significantly increased in 5/6Nx and BiNx mice 24 h post-op [SCR (mg/dl): sham 0.39 +/- 0.05, 4/6Nx 0.52 +/- 0.07, P = 0.13, 5/6Nx 1.00 +/- 0.29, P < 0.01]. In the longitudinal experiment, CYS showed the renal damage significantly earlier and to a larger extent (2 h: SCR 57 +/- 15%, BUN 40 +/- 16%, CYS 295 +/- 143%, P <0.001). CONCLUSIONS: CYS can be used as a reliable and precise marker for renal function in mouse models. CYS is more sensitive than SCR, and it shows renal damage earlier than SCR and BUN.