Chronic Kidney Disease and Pregnancy. Guideline of the DGGG, OEGGG, DGfN (S2k Level, AWMF Registry No. 015 - 090).

Aim As diagnostic and therapeutic options have improved in recent years, women with limited renal function of varying etiologies are now able to become pregnant. Depending on the extent of disease and the patients' comorbidities, the care of these women can be especially challenging. This guideline aims to improve the interdisciplinary care offered to pregnant women with kidney disease. Methods A selective literature search was carried out. This S2k guideline was then compiled using a structured consensus-based process which included representatives from different medical specialties and professional societies. Recommendations Recommendations for the care of pregnant women with renal disease were developed to cover preconception counseling, the recording of risks, special aspects of prenatal care and prenatal screening, as well as the specific treatment options for the underlying disease in women wanting to have children and pregnant women.

Interim analysis of the COSA (COVID-19 patients treated with the Seraph® 100 Microbind® Affinity filter) registry.

BACKGROUND: The Seraph® 100 Microbind® Affinity Blood Filter is a haemoperfusion device that is licensed for the reduction of pathogens, including several viruses, in the blood. It received Emergency Use Authorization for the treatment of severe coronavirus disease 2019 (COVID-19) by the Food and Drug Administration (FDA). Several studies have shown that the blood viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlates with adverse outcomes and removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph® 100 has been recently demonstrated. The aim of this registry was to evaluate the safety and efficacy of Seraph® 100 treatment for COVID-19 patients. METHODS: Twelve hospitals from six countries representing two continents documented patient and treatment characteristics as well as outcome parameters without reimbursement. Additionally, mortality and safety results of the device were reported. A total of 102 treatment sessions in 82 patients were documented in the registry. Four patients were excluded from mortality analysis due to incomplete outcome data, which were available in the other 78 patients. RESULTS: Overall, a 30-day mortality rate of 46.2% in the 78 patients with complete follow-up was reported. The median treatment time was 5.00 h (4.00-13.42) and 43.1% of the treatments were performed as haemoperfusion only. Adverse events of the Seraph® 100 treatment were reported in 8.8% of the 102 treatments and represented the premature end of treatment due to circuit failure. Patients who died were treated later in their intensive care unit (ICU) stay and onset of COVID symptoms. They also had higher ferritin levels. Multivariate Cox regression revealed that delayed Seraph® 100 treatment after ICU admission (>60 h), as well as bacterial superinfection, were associated with mortality. While average predicted mortality rate according to Sequential Organ Failure Assessment (SOFA) score in ICU patients was 56.7%, the observed mortality was 50.7%. In non-ICU patients, Coronavirus Clinical Characterisation Consortium (4C) score average predicted a mortality rate of 38.0%, while the observed mortality rate was 11.1%. CONCLUSIONS: The treatment of COVID-19 patients with Seraph® 100 is well tolerated and the circuit failure rate was lower than previously reported for kidney replacement therapy (KRT) in COVID-19 patients. Mortality correlated with late initiation of Seraph treatment after ICU admission and bacterial superinfection. Compared with predicted mortality according to 4C and SOFA scores, mortality of Seraph® 100-treated patients reported in the registry was lower.

First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.

In chronic kidney disease both renal insufficiency and chronic inflammation trigger elevated hepcidin levels, which impairs iron uptake, availability. and erythropoiesis. Here we report the two first-in-human phase 1 trials of PRS-080#22, a novel, rationally engineered Anticalin protein that targets and antagonizes hepcidin. A single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients with end stage chronic kidney disease (CKD) on hemodialysis (phase 1b) at different doses (0.08-16mg/kg for the phase 1a study and 2-8mg/kg for the phase 1b study) in successive dosing cohorts. The primary endpoint for both randomized, double-blind, phase 1 trials was safety and tolerability. Following treatment, all subjects were evaluable, with none experiencing dose limiting toxicities. Most adverse events were mild. One serious adverse event occurred in the phase 1b (CKD patient) study. There were no clinically significant changes in safety laboratory values or vital signs. PRS-080#22 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately three days in healthy volunteers and 10 to 12 days in CKD patients. Serum hepcidin levels were suppressed in a dose dependent manner and remained low for up to 48 hours after dosing. PRS-080#22 dose-dependently mobilized serum iron with increases in both serum iron concentration and transferrin saturation. No consistent changes were observed with regard to ferritin, reticulocytes, hemoglobin, and reticulocyte hemoglobin. Low titer anti-drug-antibodies were detected in five healthy volunteers but in none of the CKD patients. PRS-080#22, a novel Anticalin protein with picomolar affinity for hepcidin, was safe and well-tolerated when administered to healthy volunteers and CKD patients at all doses tested. The drug exhibited linear pharmacokinetics, longer half-life in CKD patients in comparison to healthy volunteers as well as expected pharmacodynamic effects which hold promise for further clinical studies.

Gadolinium-based contrast media compared with iodinated media for digital subtraction angiography in azotaemic patients.

BACKGROUND: To determine whether gadolinium-based contrast media (CM) could be used safely for angiographies in patients with renal dysfunction we investigated renal function after gadobutrol exposure and compared the results with standard iodinated CM (iohexol) in a randomized clinical study. METHODS: Twenty-one patients (aged 67+/-11 years, nine female and 12 male) with severely impaired renal function [mean serum creatinine 3.2+/-1.3 mg/dl, mean glomerular filtration rate (GFR) 31+/-16 ml/min/1.73 m(2)] who needed to have angiography because of severe peripheral vascular disease, renal artery stenosis or aortic aneurysms were randomized to receive in a blinded manner either gadobutrol (Gadovist 1.0 mmol/ml) or iohexol (Omnipaque 350) as contrast agents. GFR was measured by CM clearance (Renalyzer) at baseline and 48 h after CM administration. The primary end point was the mean change of GFR from baseline at 48 h, the secondary one the incidence of CM-induced acute renal failure, defined as a decrease in GFR of >50% from baseline within 48 h of CM administration. RESULTS: In the gadobutrol group (n = 10) we observed a statistically significant decrease in GFR of 10.6+/-13.8 ml/min/1.73 m(2) within 48 h after CM administration (P<0.05, paired t test). The incidence of CM-induced ARF amounted to 50%. In comparison, the iohexol group (n = 11) also showed a statistically significant GFR reduction of 8.7+/-8.8 ml/min/1.73 m(2) (P<0.05, paired t test), and of ARF by 45%. The percentile of differences of GFR decreases between the two groups was not significant (P = 0.70). No patient demonstrated other adverse effects of gadobutrol or iohexol administration, apart from GFR reduction. Despite the decline in GFR, no patient required haemodialysis in the 10 following days. CONCLUSIONS: In our study, gadolinium-based angiography showed no benefit over iohexol angiography with respect to preventing GFR reduction in patients with severely impaired renal function.

Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains.

BACKGROUND: Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulointerstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. The chromosomal locus for MCKD2 was localized on chromosome 16p12. Within this chromosomal region, Uromodulin (UMOD) was located as a candidate gene. UMOD encodes the Tamm-Horsfall protein. By sequence analysis, one group formerly excluded UMOD as the disease-causing gene. In contrast, recently, another group described mutations in the UMOD gene as responsible for MCKD2 and familial juvenile hyperuricemic nephropathy (FJHN). METHODS: Haplotype analysis for linkage to MCKD2 was performed in 25 MCKD families. In the kindreds showing linkage to the MCKD2 locus on chromosome 16p12, mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. RESULTS: In 19 families, haplotype analysis was compatible with linkage to the MCKD2 locus. All these kindreds were examined for mutations in the UMOD gene. In three different families, three novel heterozygous mutations in the UMOD gene were found and segregated with the phenotype in affected individuals. Mutations were found only in exon 4. CONCLUSION: We confirm the UMOD gene as the disease-causing gene for MCKD2. All three novel mutations were found in the fourth exon of UMOD, in which all mutations except one (this is located in the neighboring exon 5) published so far are located. These data point to a specific role of exon 4 encoded sequence of UMOD in the generation of the MCKD2 renal phenotype.

Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.

OBJECTIVE: Angiotensin-converting enzyme inhibitors (ACEI) show an antiproteinuric and thus nephroprotective effect in patients suffering from glomerulonephritis. Angiotensin II-receptor-antagonists (AT1RA) are also efficacious in reducing proteinuria. The study was performed to investigate the antiproteinuric effect of AT1RA candesartan in patients diagnosed with chronic glomerulonephritis by biopsy, and who were already being treated with an ACEI. METHODS: A total of 12 patients with a persistent proteinuria of at least 1 g/day who were already being treated with an ACEI for more than 3 months were included. The study was performed using a double-blind, placebo-controlled and randomized method with two treatment periods of 8 weeks (placebo or candesartan 8 mg/day) and a wash-out period of 4 weeks in between. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin- and PAH-clearances at the beginning and the end of each treatment period. RESULTS: Proteinuria significantly decreased from 2 +/- 0.4 g/day to 1.3 +/- 0.3 g/day (P < 0.05) with the addition of candesartan treatment, whereas it remained unchanged (from 1.8 +/- 0.3 g/day to 1.9 +/- 0.3 g/day) under placebo. GFR (candesartan: from 66 +/- 13 to 58 +/- 11 ml/min per 1.73 m2, placebo: from 64 +/- 11 to 62 +/- 13 ml/min per 1.73 m2) and ERPF (candesartan: from 329 +/- 44 to 304 +/- 37 ml/min per 1.73 m2, placebo: from 362 +/- 48 to 315 +/- 46 ml/min per 1.73 m2) did not alter significantly after 8 weeks of treatment. The addition of candesartan treatment significantly reduced systolic blood pressure (from 129 +/- 3 to 123 +/- 2 mmHg, P < 0.05) and diastolic blood pressure (from 79 +/- 2 to 76 +/- 2 mmHg, P < 0.05) compared with placebo (systolic: 128 +/- 3 to 127 +/- 3 mmHg, diastolic: 79 +/- 2 to 79 +/- 2 mmHg). CONCLUSION: Candesartan promotes a complementary antiproteinuric and a small antihypertensive effect after a treatment period of 8 weeks in patients with chronic glomerulonephritis when given in conjunction with an ACEI. Renal hemodynamics did not vary significantly.

Changes in renal and systemic hemodynamics after NO-synthase inhibition in males with family history of hypertension.

BACKGROUND: Nitric oxide (NO) plays an important role in the regulation of blood pressure and renal hemodynamics. METHODS: To further investigate the role of NO in human hypertension, we studied the effect of systemic injection of N(G)-monomethyl-L-arginine (L-NMMA) on renal hemodynamics, urinary sodium excretion (FE(Na)), systemic hemodynamics and several vasoactive hormones in 5 healthy male subjects with (group H) and without (group N) family history of hypertension. An intravenous infusion of L-NMMA (3 mg/kg over 10 min) or placebo was given in a randomized, double-blinded manner. GFR and ERPF were measured by inulin- and PAH-clearances. Norepinephrine infusion (0.1 microg/kg/min over 60 min) served as vasoconstrictive control infusion. RESULTS: L-NMMA induced a significant decrease in ERPF (-135 +/- 49 vs. 7 +/- 31 ml/min/1.73 m(2) with placebo, p < 0.05), a decrease in FE(Na) (-1.2 +/- 0.6% with L-NMMA vs. 0.0 +/- 0.1% with placebo), and a significant increase in diastolic blood pressure (+7 +/- 1 vs. -2 +/- 1 mm Hg with placebo) in group N, only. A sustained drop in plasma renin activity (-0.1 +/- 0.1 vs. 0.3 +/- 0.1 ng/ml/h with placebo) could also be seen in this group, only. Subjects with family history of hypertension showed minor or even no response (changes in diastolic blood pressure: L-NMMA: 5 +/- 3 mm Hg, placebo: 0 +/- 2 mm Hg; changes in ERPF: L-NMMA: -89 +/- 57 ml/min/1.73 m(2), placebo: -34 +/- 28 ml/min/1.73 m(2); changes in plasma renin activity: L-NMMA: -0.0 +/- 0.3 ng/ml/h, placebo: -0.1 +/- 0.2 ng/ml/h). The vasoconstrictive effect of norepinephrine infusion did not differ between both groups. CONCLUSION: Our data indicate that systemic NO synthetase inhibition by L-NMMA results in a blunted effect on systemic blood pressure and the renal hemodynamic system in subjects with family history of hypertension.