Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment.

BACKGROUND: 5q-associated spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons with consecutive weakness and atrophy of the limb, respiratory, and bulbar muscles. While trunk and limb motor function improve or stabilize in adults with SMA under nusinersen and risdiplam treatment, the efficacy on bulbar function in this age group of patients remains uncertain. However, it is important to assess bulbar dysfunction, which frequently occurs in the disease course and is associated with increased morbidity and mortality. METHODS: Bulbar function was evaluated prospectively in 25 non-ambulatory adults with type 2 and 3 SMA before and 4 and 12 months after risdiplam treatment initiation using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (b-ALSFRS-R). Extremity function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). RESULTS: Subjective swallowing quality, measured with the SSQ, improved after 12 months of therapy with risdiplam. For the b-ALSFRS-R, a non-significant trend towards improvement was observed. The RULM score improved after 12 months of risdiplam therapy, but not the HFMSE score. HFMSE and RULM scores did not correlate with the SSQ but the b-ALSFRS-R score at baseline. CONCLUSIONS: The improvement in subjective swallowing quality under risdiplam treatment, despite an advanced disease stage with severe motor deficits, strengthens the importance of a standardized bulbar assessment in addition to established motor scores. This may reveal relevant treatment effects and help individualize treatment decisions in the future.

Objective measurement of oral function in adults with spinal muscular atrophy.

BACKGROUND: Impairment of bulbar function in adult individuals with spinal muscular atrophy (SMA) usually is not assessed by established motor scores. Measurements of oral function including quantitative muscle and endurance tests are able to detect subtle changes. The aim of this study was to systematically evaluate the measurement of maximum bite force and endurance, maximum tongue pressure and endurance, as well as maximum mouth opening in adult individuals with SMA types 2 and 3. METHODS: Data from oral function tests in 43 individuals were analyzed. Differences in oral function between individuals with different SMA types and numbers of SMN2 copies were tested. Spearman´s rho correlations among oral function measures themselves as well as with established clinical outcome scales were analyzed. RESULTS: The absolute maximum measures of oral function (maximum bite force, maximum tongue pressure, maximum mouth opening) were able to discriminate between individuals with different SMA types, individuals with a different number of SMN2 copies and with different walking abilities. The pairwise correlations of the absolute maximum measures of oral function were fair to moderate in size; the same was true for their correlations with the established motor scores. All correlations assessing endurance measures of oral function were weaker and statistically insignificant. CONCLUSIONS: Among the oral function tests maximum tongue pressure and maximum mouth opening are particulary promising as clinical and sensitive outcome measures for clinical trials. Oral function tests may supplement existing motor scores, in particular concerning specific questions about bulbar function or in severely affected non-ambulatory individuals where mild (treatment-related) changes would otherwise remain undetected. Trial registration DRKS, DRKS00015842. Registered 30 July 2019, https://drks.de/search/de/trial/DRKS00015842.

Late Conversion to Belatacept After Kidney Transplantation: Outcome and Prognostic Factors.

BACKGROUND: Conversion to belatacept at a later point after kidney transplantation (KT) as a rescue therapy has been shown to be beneficiary in an increasing number of patients, but prognostic factors for a favorable outcome have never been investigated. METHODS: The present study analyzed all KT patients after late conversion to belatacept in a single center regarding graft survival and changes in estimated glomerular filtration rate (eGFR), proteinuria, and mean fluorescence intensity (MFI) of donor-specific antibodies (DSA). RESULTS: A total of 69 KT patients were converted to belatacept. eGFR increased from 28.9 ± 18.2 mL/min/1.73 m2 at time of conversion to 34.8 ± 20.1 mL/min/1.73 m2 after 18 months (P = .025). After conversion, 26/69 patients (37.7%) showed a sustained increase in eGFR of >5 mL/min/1.73 m2 after 12 months and were defined as responders. All other patients (43/69, 62.3%) were defined as nonresponders. In multivariate analysis, nonresponders presented with significantly higher proteinuria (552 ± 690 vs 165 ± 158 mg/L; P = .004) at the time of conversion. Changes of eGFR from before conversion and the time of conversion were similar in both subgroups (-5.7 ± 9.2 and 29.2 ± 17.3 mL/min/1.73 m2 in responders and -4.6 ± 10.7 and 28.7 ± 19.0 mL/min/1.73 m2 in nonresponders). HLA antibody panel reactivity did not change after conversion. DSA-MFI was higher in nonresponders (7,155 ± 6,785) than in responders (2,336 ± 2,173; P = .001). One patient (1/69, 1.4%) developed de novo DSA after conversion, and no antibody-mediated rejection was diagnosed within 1,540 treatment months. CONCLUSIONS: Late conversion to belatacept is beneficiary for a subgroup of patients, with lower proteinuria at the time of conversion being an indicator for a favorable outcome.

Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae-Related Urinary Tract Infection in Kidney Transplant Recipients: Risk Factors, Treatment, and Long-Term Outcome.

BACKGROUND: Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) has risen in kidney transplant (KT) patients, with no long-term data so far on graft function or survival. METHODS: KT patients with ESBL-E-positive urine culture were retrospectively analyzed regarding initial adequate antimicrobial therapy, recurrent infection, transplant function, and survival compared with an ESBL-E-negative KT control cohort. RESULTS: ESBL-E-positive KT patients (n = 93) were older (55.5 ± 16.1 vs 49.5 ± 16.8 y; P = .001), presented with higher trough levels of cyclosporine and tacrolimus (121 ± 71 vs 102 ± 32 ng/mL [P = .04]; and 7.9 ± 3.3 vs 7.0 ± 2.3 ng/mL [P = .04], respectively), higher dosages of mycophenolate (1,533 ± 670 vs 1,493 ± 436; P = .001), and more acute rejection episodes within 3 months before diagnosis (12.9% vs 0.8%; P < .0001) compared with control subjects (n = 591). Five-year patient survival was superior in control subjects compared with ESBL-E-positive patients (91.2% vs 83.5%; P = .034) but long-term graft function was similar. Hospitalization rates were higher in patients presenting with ESBL-E-related urinary tract infection (UTI) compared with control subjects with ESBL-E-negative UTI (60.3% vs 31.3%; P = .002) but 5-year graft survival was superior in patients presenting with ESBL-E-related UTI (88.6% vs 69.8%; P = .035) compared with control subjects with ESBL-E-negative UTI. Recurrence rates were similar in patients with or without ESBL-E-related UTI. Initial antibiotic treatment was adequate in 41.2% of patients presenting with ESBL-E-related urosepsis, resulting in a reevaluation of antibiotic stewardship in our clinic. CONCLUSIONS: ESBL-E detection in general was associated with higher mortality, but graft survival in patients with ESBL-E-related UTI was significantly better compared with ESBL-E-negative UTI.

Treatment of renal angiomyolipoma in tuberous sclerosis complex (TSC) patients.

In adult tuberous sclerosis complex (TSC) patients, renal complications are the leading cause of death. Beginning in childhood, up to 80 % of patients develop renal angiomyolipoma characterized by a size-dependent risk of life-threatening bleeding. After discovery of the two causative genes, TSC1 and TSC2, and the role of mammalian target of rapamycin (mTOR) regulation in the pathogenesis of TSC, an increasing number of clinical studies evaluating mTOR inhibition in TSC patients have shown impressive results in many organ manifestations, such as brain, lung, and kidney. For renal angiomyolipoma, mTOR inhibitor treatment fundamentally changed the approach from preventive embolization or even partial nephrectomy to everolimus treatment in order to preserve kidney function.

Successful Recovery of Acute Renal Transplant Failure in Recurrent Hepatitis C Virus-Associated Membranoproliferative Glomerulonephritis.

Recurrence of hepatitis C virus (HCV)-associated membranoproliferative glomerulonephritis (MPGN) in the kidney transplant may lead to continuous graft deterioration and the need for further renal replacement therapy. The novel direct-acting antiviral agents (DAAs) allow a highly effective and interferon-free treatment option for chronic HCV-infected patients. Data on the therapeutic safety and efficacy in HCV-infected renal transplant patients are sparse, especially for patients with severe renal impairment. We report the case of a 63-year-old female HCV-positive renal transplant patient with biopsy-proven recurrence of MPGN in the renal graft 3 years after transplant. Because of rapid loss of transplant function and consecutive need for hemodialysis, we initiated a combined anti-HCV-directed therapy regimen consisting of daclatasvir and simeprevir over 12 weeks. Viral clearance of HCV was obtained as early as 2 weeks after start of treatment. No adverse therapy-associated side effects were observed, and immunosuppressive dosing remained unchanged. Importantly, graft function fully recovered and hemodialysis was stopped 2 mo after the end of daclatasvir/simeprevir treatment. We report the first case of successful recovery of dialysis-dependent renal transplant failure after treatment of recurrent HCV-associated MPGN in a kidney transplant recipient by curing the underlying HCV infection with a combination of novel DAAs.

[Sporadic Lymphangioleiomyomatosis (sLAM) and Tuberous Sclerosis Complex (TSC) - Pulmonary Manifestations]. / Sporadische Lymphangioleiomyomatose (sLAM) und Tuberöse-Sklerose-Komplex (TSC) ­ Pulmonale Manifestationen.

Lymphangioleiomyomatosis (LAM) is a rare multi-system disorder affecting predominantly women of childbearing age. The disease entity is divided in sporadic LAM (sLAM) and LAM associated with tuberous sclerosis complex (TSC). In up to 50 % of female TSC-patients pulmonary involvement (TSC-LAM) can be found, with first clinical symptoms usually starting between 25 and 30 years of age. Progressive deterioration of lung function of 3 - 11 % of diffusion capacity per year has been described, that's why all female TSC patients should be screened for LAM (pulmonary function testing, 6-minute walk test, high-resolution chest CT scan). MTOR inhibitors such as Everolimus or Sirolimus are implemented in the treatment of TSC/LAM and found to control disease burden. Screening for all organ manifestations in TSC is recommended and allows to improve prognosis and to prevent complications in TSC.

Risk Evaluation and Outcome of Pneumocystis jirovecii Pneumonia in Kidney Transplant Patients.

Pneumocystis jirovecii pneumonia (PJP) affects immunocompromised patients. As a result of effective prophylaxis in the 1st months after kidney transplantation, PJP is increasingly diagnosed in the long term after transplantation. The present study evaluates course and outcome of PJP in a single transplant center from 2010 to 2015. Twenty-three patients presented with PJP at a mean of 53.7 ± 50.2 months after transplantation. Of these, 3 patients underwent ABO-incompatible (ABO-i) living-donor transplantation and 3 patients were treated with the use of belatacept. For risk estimation, 3 control cohorts were defined: a control group of all kidney transplant patients presenting for routine follow up (n = 575), all patients transplanted in an ABO-i setting (n = 45), and all patients treated with belatacept in our clinic (n = 69). Mortality in patients with PJP was 3/23 (13%) and graft loss after PJP was 3/23 (13%) resulting in patient and graft survivals of 87% and 73.9%, respectively. All patients were without PJP prophylaxis at time of diagnosis. Five of the 23 PJP patients received rejection therapy or dose escalation of immunosuppression 6 months before PJP infection, and 1 patient experienced acute rejection within 6 months after PJP treatment. In the course of PJP, 8 patients developed acute respiratory insufficiency. At time of PJP diagnosis, patients presented with severe lymphopenia (mean ± SD lymphocyte count, 0.64 ± 0.27/nL; normal range: 1.5-3/nL). Patients after ABO-i transplantation, as well as patients treated with belatacept, showed an increased risk for PJP (7.3% and 4.3%, respectively); however, in belatacept patients, other risk factors, such as age, low estimated glomerular filtration rate (eGFR), and lymphopenia seemed to contribute to this increased risk.

Living Donor Transplantation: Long-Term Evolution Related to Age Matching.

The lack of donors is favoring living kidney donor (LKD) transplantation worldwide, quite often beyond the classic age-matching rules. We analysed renal function (RF) at 1 and 5 years in all donor and recipients as well as death-censored graft and patient survival. LKD recipients were divided into 4 subgroups: young recipients-young donors (YR-YD; N = 355), elderly recipients-young donors (ER-YD; N = 13), young recipients-elderly donors (YR-ED; N = 67), and elderly recipients-elderly donors (ER-ED; N = 38). "Elderly" was defined as ≥60 years. RF was better in those who received a young allograft (YR-YD/ER-YD) at any time (P < .001). There was a trend toward higher proteinuria among the recipients of an old allograft (YR-ED/ER-ED) at any time (P = not significant [NS]). However, our population showed low levels of proteinuria and this was not a risk factor for graft failure. Logistic regression model showed that creatinine level at 1 year is a good predictor of graft losses. Graft survival was worse in the allografts from elderly donors (P < .001). Analysing the young recipients, renal survival was inferior in those who received an old kidney (YR-ED; P < .00005) as well as mortality rates at 14 years (P = .03). The RF of young (N = 295) and elderly donors (N = 98) was optimal with no progression to ESRD or deaths registered during follow-up. In conclusion, young recipients of elderly kidneys pay the price of a worse RF, allograft prognosis, and patient prognosis. The pair YR-ED is a doable option, but we recommend age matching when it is possible.

[Immunosuppression and its use in kidney transplantation]. / Immunsuppression und Ergebnisse in der Nierentransplantation.

BACKGROUND: Current immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality. OBJECTIVES: The purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival. METHODS: Review of the current topic-related literature and discussion of our own experience. RESULTS: The use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials. CONCLUSIONS: Current immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.

Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation.

Donor-specific HLA antibodies (DSA) have a negative impact on kidney graft survival. Therefore, we analyzed the occurrence of DSA and antibody-mediated rejection (AMR) in patients from two prospective randomized trials in our center. At 3-4.5 months posttransplant 127 patients were randomized to continue cyclosporine or converted to everolimus therapy. The presence of DSA was prospectively assessed using Luminex assays. AMR was defined according to the Banff 2009 classification. Antibody screening was available in 126 patients with a median follow-up of 1059 days. Seven out of 65 (10.8%) patients on cyclosporine developed DSA after a median of 991 days. In comparison, 14/61 patients (23.0%) randomized to everolimus developed DSA after 551 days (log-rank: p = 0.048). Eight patients on everolimus compared to two patients on cyclosporine developed AMR (log-rank: p = 0.036). Four of 10 patients with AMR-all in the everolimus group-lost their graft. A multivariate regression model revealed everolimus, >3 mismatches and living donor as significant risk factors for DSA. Acute rejection within the first year, >3 mismatches, everolimus and living donor were independent risk factors for AMR. This single center analysis demonstrates for the first time that everolimus-based immunosuppression is associated with an increased risk for the development of DSA and AMR.

Dent's disease: identification of a novel mutation in the renal chloride channel CLCN5.

Dent's disease is an inherited tubulopathy caused by a mutation in the CLCN5 chloride channel gene. It is characterized by low-molecular weight proteinuria, hypercalciuria, nephrolithiasis or nephrocalcinosis, rickets and eventual-progressive renal failure. Onset of clinical symptoms show a great variability, making a diagnosis at an early stage of the disease often difficult. Given the variably clinical picture, genetic analysis can provide a reliable method to confirm the diagnosis. Here, we report on the case of a patient with progressive renal failure showing signs of a tubular lesion and symptoms of Dent's disease. Although this rare disease was suspected by means of the clinical features, it was genetic analysis that confirmed the diagnosis and revealed a novel mutation in the CLCN5 gene.

Regulation of pressure-activated channel in intact vascular endothelium of stroke-prone spontaneously hypertensive rats.

The pressure-activated cation channel (PAC), a novel type of mechanosensitive channel, has been suggested to act as a mechanosensor in aortic endothelium. In experimental hypertension, PAC function was up-regulated in the established phase of high blood pressure. This association of altered PAC function and elevated arterial pressure suggests that PAC function is regulated by alterations in blood pressure. In the present study, we electrophysiologically investigated PAC function in intact endothelium of aorta (EA) and mesenteric artery (EMA) from stroke-prone spontaneously hypertensive rats (SHRSP), SHRSP after 4 weeks of treatment with quinaprilat (10 mg/kg/day), and normotensive Wistar-Kyoto (WKY) rats. In untreated SHRSP and WKY rats, systolic blood pressure (SBP) was 201+/-3 mm Hg and 142+/-3 mm Hg, respectively. In quinaprilat-treated SHRSP, SBP was lowered to 135+/-5 mm Hg. Apparent PAC density (percentage of patches with PAC activity) in EA of untreated SHRSP (63.7%+/-7.3%) was 2.4-fold higher than in WKY rats (26.0%+/-5.0%). In contrast, no significant PAC up-regulation was detected in EMA of SHRSP (15.7%+/-4.2%) compared with WKY rats (12.0%+/-3.9%). In EA of quinaprilat-treated normotensive SHRSP, PAC density (27.1%+/-5.2%) was lowered to levels found in normotensive WKY rats. Unitary conductance and pressure sensitivity of PAC were not altered in either hypertensive or normotensive rats. Taken together, hypertension-induced increases of endothelial PAC density can be completely reversed by antihypertensive therapy. The PAC up-regulation in EA was interpreted as a compensatory mechanism to enhance Ca2+-influx and subsequently the synthesis of vasodilatory factors. This mechanism is missing in EMA of SHRSP, which might contribute to high blood pressure in this rat model of severe genetic hypertension.

Impaired hyperpolarization in regenerated endothelium after balloon catheter injury.

Ca(2+)-activated K(+) (K(Ca)) channels control endothelial Ca(2+) homeostasis and the formation of vasodilators. After angioplasty, dysfunction of the regenerated endothelium leads to abnormal vasoregulation. In this study, we tested the expression and function of K(Ca) channels in regenerated endothelium at 6 weeks after balloon catheter injury of rat carotid arteries (CAs) by using single-cell reverse transcription-polymerase chain reaction, patch-clamp techniques, and analysis of vasoreactivity. In single regenerated endothelial cells (ECs), the percentage of ECs expressing the K(Ca) genes, rSK3 (12+/-8%) and rIK1 (22+/-9%), was significantly lower compared with the percentage of native ECs expressing these genes (rSK3 58+/-8%, rIK1 64+/-10%). In patch-clamp experiments, K(Ca) currents and acetylcholine-induced hyperpolarization were markedly reduced in regenerated ECs (shift of membrane potential -6+/-3 mV) compared with those in native ECs (shift of membrane potential -21+/-5 mV). In pressure myograph experiments, acetylcholine-induced dilation was impaired in reendothelialized CAs compared with normal CAs. Intraluminal application of the K(Ca) blocker apamin and charybdotoxin inhibited dilation by 30% in normal CAs but was without effect in reendothelialized CAs. Intraluminal application of 1-ethyl-2-benzimidazolinone (100 micromol/L), an opener of K(Ca) channels, evoked dilation by 29% in normal CAs but had no effect in reendothelialized CAs. In conclusion, the impaired expression of K(Ca) channels in regenerated endothelium results in defective hyperpolarization and impaired dilation. Thus, the impaired K(Ca) channel function contributes to functional alterations of regenerated endothelium after angioplasty.

Expression of ryanodine receptor type 3 and TRP channels in endothelial cells: comparison of in situ and cultured human endothelial cells.

OBJECTIVE: Ca(2+) mobilization plays an important role in endothelial function by stimulating Ca(2+)-dependent synthesis of vasodilating factors. In addition to inositol-1,4,5-trisphosphate (InsP(3)) mediated Ca(2+) mobilization, Ca(2+) release from ryanodine-sensitive pools and Ca(2+)-influx through TRP channels have been suggested to be important in endothelial Ca(2+)-signaling. However, the function and molecular identity of TRP channels and ryanodine receptors in human endothelium in situ are still elusive. We hypothesized that expression of ryanodine-receptors (RyR) and TRP channels differs between human endothelium in situ and in cultured cells. METHODS: By combining single-cell RT-PCR and patch-clamp techniques, expression of RyR and TRP channels was determined in situ in endothelial cells of human mesenteric artery (HMAECs) obtained from patients undergoing bowel resection and in the endothelial cell line EA.hy926. RESULTS: At the single cell level, expression of RyR 3 was detected in 25 and 5% of HMAECs and EA.hy926 samples, respectively. Expression of the RyR 1 and 2 was not detected in either HMAECs or EA.hy926. In patch-clamp experiments in HMAECs, applications of caffeine (0.5 mM) induced sustained hyperpolarization mediated by activation of Ca(2+)-activated K channels. In EA.hy926, caffeine-induced hyperpolarization was not detected. Single HMAECs expressed the TRP genes, TRP1 and TRP3, but not TRP 4 and 6. The TRP1 was the predominantly expressed TRP gene in HMAECs in situ whereas TRP3 expression was rarely detected. EA.hy926 expressed only TRP1. In patch clamp experiments in HMAECs, Ca(2+)-store depletion activated non-selective cation currents leading to Ca(2+) entry. CONCLUSIONS: Our findings suggest that, in addition to InsP(3) mediated Ca(2+) release, Ca(2+) release from ryanodine-sensitive stores mediated by RyR3 and Ca(2+) entry through TRP1 might represent important components of endothelial Ca(2+) signaling in situ and thereby of endothelial function in intact human blood vessels.