Acute leg pain and weakness in pregnancy: A new diagnosis of myotonic dystrophy.

We present a unique case of a 44-year-old woman who presented at 29 weeks' gestation with proximal limb pain and elevated creatine kinase. This occurred in the background of premature cataracts, atrial fibrillation and abnormal liver function. Clinical, pathological and neurodiagnostic findings supported a diagnosis of myotonic dystrophy, confirmed by genetic testing which revealed dystrophia myotonica protein kinase gene expansion. Muscle biopsy found both recent necrotising and chronic myopathic processes. Following delivery, the mother's myalgia resolved and creatine kinase quickly declined. The fetus was diagnosed with congenital myotonic dystrophy. We review the impact of myotonic dystrophy on pregnancy and discuss potential explanations for this patient's clinical course. This case emphasises the importance of considering myotonic dystrophy as a differential diagnosis in the right clinical context and the need for pre-pregnancy assessment and genetic counselling in women with known myotonic dystrophy.

Management of chronic rheumatic diseases in women 18-45 years of age in Asia Pacific: insights from patient and clinician surveys.

OBJECTIVE: Perspectives of women aged 18-45 years with chronic rheumatic diseases (CRD), and clinicians, in the Asia-Pacific (APAC) region are reported. METHODS: Online surveys were completed by women, pregnant in the past 2-5 years, with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), and rheumatologists, obstetricians, orthopaedic surgeons who medically manage CRDs. RESULTS: Among 210 (RA 122, PsA 48, axSpA 40) patients, 52% (n = 109/210) delayed their decision to have children, most commonly due to concerns of passing on disease to offspring. 33% (n = 70/210) discussed family planning with a healthcare professional at diagnosis. Patients most often initiated discussions. 94% (n = 193/205) stopped treatment around pregnancy due to fear of fetal harm. 66% (n = 139/210) of patients felt they did not receive all relevant information on the impact of CRDs and treatment on pregnancy. Among 335 clinicians who participated, 82% (n = 143/174) of rheumatologists, 86% (n = 72/84) of obstetricians and 43% (n = 33/77) of orthopaedic surgeons agreed good disease control during pregnancy was their primary goal. 69% (n = 120/174) of rheumatologists were 'very comfortable' with prescribing tumour necrosis factor inhibitors (TNFi) for women aged 18-45 years. Comfort levels generally decreased with the onset of family planning. More obstetricians and orthopaedic surgeons supported avoiding TNFi during pregnancy than rheumatologists (40% [n = 34/84]/38% [n = 29/77] versus 16% [n = 28/174]). Access to more TNFi safety data during pregnancy was considered paramount for increasing clinician comfort. CONCLUSIONS: Patients and physicians need current information and multidisciplinary discussions for improved management of CRD in women in APAC.

Successful Implementation of an Increased Viral Risk Donor Waiting List for Preconsented Kidney Transplant Candidates in Victoria, Australia.

Increased viral risk donors (IVRDs) with increased risk behaviors for blood-borne virus infection and negative nucleic acid testing have a low absolute risk of "window period" infection. Utilization and allocation of IVRD organs differ between jurisdictions. METHODS: We examined the characteristics and utilization of deceased donor IVRD kidneys and recipient outcomes within a 2-y period (July 31, 2018-July 31, 2020) postimplementation of a new opt-in allocation pathway for preconsented recipients in Victoria, Australia. RESULTS: Fifty-six kidneys from 31 IVRDs were utilized, comprising 13% of donors. Preconsent rate to accept IVRD kidneys increased to 41% of the waitlist in the 2 y postimplementation, and IVRDs having no kidneys utilized reduced to 0%. Compared with non-IVRD kidneys, kidney offer declines >10 per donor were less likely from IVRDs (3% vs 19%; P < 0.05). IVRDs were younger (median age 36 [IQR 30-44] vs 51 [35-60] y; P < 0.0001), with lower kidney donor profile index (25% [13-40%] vs 57% [29-75%]; P < 0.0001), and less hypertension (0% vs 22%; P < 0.01). Estimated glomerular filtration rate 3 mo post-transplant was superior (P < 0.01). Injecting drug use (61%) was the most common increased risk behavior. 29% of IVRDs were hepatitis C antibody positive but nucleic acid testing negative. No active infection was detected in any recipient post-transplant. CONCLUSIONS: The described opt-in system permits efficient allocation and utilization of kidneys from IVRDs, with superior quality and graft function. Education is crucial to facilitate informed consent and equity of access to this donor pool.

Dialysis and driving: an anonymous survey of patients receiving dialysis for end-stage kidney disease.

BACKGROUND: Driving is a complex task requiring multiple cognitive domains and the musculoskeletal system. Cognitive dysfunction is associated with driving impairment. Dialysis patients are known to have a high prevalence of cognitive impairment and other comorbidities, and may be at risk of driving impairment. No Australian guidelines address driving safety in dialysis patients. AIMS: To estimate the proportion of dialysis patients who were driving and those at risk of driving impairment, and to investigate the agreement between objective and subjective markers of risk. METHODS: This single-centre study involved dialysis patients voluntarily completing two questionnaires relating to risk of driving impairment; the first questionnaire focussed on objective markers, and the second questionnaire focussed on subjective markers. Risk of driving impairment was established using pre-determined criteria, and the agreement between objective and subjective markers was estimated using Cohen kappa. RESULTS: A total of 44.8% (99/221) of patients participated; 76.8% (76/99) of participants were driving, and 76.3% (58/76) of drivers were at risk of driving impairment. Factors associated with at-risk driving included post dialysis dizziness, leg weakness or numbness, falling asleep while driving and hypoglycaemia. Sixteen patients reported collisions since commencing dialysis. The questionnaires displayed slight agreement (Cohen kappa = 0.20) between objective and subjective markers. CONCLUSIONS: Dialysis patients are at risk of driving impairment based on self-reported questionnaire responses. Discrepancies between patients' perceptions and objective markers were apparent. Further research into appropriate risk assessments, as well as development of guidelines to aid in determining driving safety in dialysis patients, is needed.

Management of thrombotic microangiopathy in pregnancy and postpartum: report from an international working group.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.

Ganciclovir-resistant post-transplant cytomegalovirus infection due to combined deletion mutation at codons 595-596 of the UL97 gene.

The development of antiviral-resistant cytomegalovirus (CMV) infection complicates the management of transplant recipients. We describe the case of a 65-year-old male who developed CMV disease on valganciclovir prophylaxis (donor CMV IgG positive, recipient CMV IgG indeterminate) 30 days after combined liver-kidney transplantation for alcoholic cirrhosis and hepato-renal syndrome. After an initial complete response to treatment dose oral valganciclovir, he developed recurrent CMV viraemia. Resistance testing revealed a UL97 mutation with in-frame deletions of codons 595-596. He was treated successfully with foscarnet and reduction in immunosuppression. This mutation has not been described previously and was suspected to confer ganciclovir resistance. Ganciclovir resistance occurs most commonly due to mutations in the UL97 or UL54 genes, which encode a protein kinase and a DNA polymerase, respectively. The UL97-encoded protein kinase phosphorylates ganciclovir to ganciclovir triphosphate, which competitively inhibits viral replication. Mutations in the UL97 gene are typically point mutations or deletions. We describe a new mutation, del595-596 in the CMV UL97 gene, occurring in the context of clinical treatment failure with standard and double-dose ganciclovir, and successful virological control achieved with foscarnet. This mutation is likely to result in ganciclovir resistance, although recombinant phenotyping is required for confirmation.

Pre-eclampsia is associated with altered expression of the renal sodium transporters NKCC2, NCC and ENaC in urinary extracellular vesicles.

Pre-eclampsia is a hypertensive disorder of pregnancy characterised by hypertension and sodium retention by the kidneys. To identify changes in sodium uptake proteins in the tubules of the distal nephron, we studied their expression in urinary extracellular vesicles or exosomes (uEVs). Urine was collected from women with pre-eclampsia or during normal pregnancy, and from healthy non-pregnant controls. uEVs were isolated by centrifugation and analyzed by Western blot. Expression, proteolytic cleavage and phosphorylation was determined by densitometric analysis normalized to the exosome marker CD9. Results showed a significant increase in phosphorylation of the activating S130 site in NKCC2, the drug target for frusemide, in women with pre-eclampsia compared with normal pregnant women. Phosphorylation of the activating sites T101/105 in NKCC2 was similar but the activating T60 site in NCC, the drug target for thiazide diuretics, showed significantly less phosphorylation in pre-eclampsia compared with normal pregnancy. Expression of the larger forms of the α subunit of ENaC, the drug target for amiloride, was significantly greater in pre-eclampsia, with more fragmentation of theγ subunit. The differences observed are predicted to increase the activity of NKCC2 and ENaC while reducing that of NCC. This will increase sodium reabsorption, and so contribute to hypertension in pre-eclampsia.

A rare cause of hypertension in pregnancy: Phaeochromocytoma.

A 26-year-old primigravida at 35 weeks' gestation was transferred to our institution from a regional hospital for management of presumed preeclampsia. Due to the labile nature of her hypertension, further investigation was undertaken which revealed a right-sided phaeochromocytoma. Alpha blockade was commenced, and an uncomplicated elective caesarean delivery was performed at 38 weeks' gestation under spinal anaesthetic. The patient underwent an elective right laparoscopic adrenalectomy six weeks post-partum. This case highlights the importance of investigating young women for secondary causes of hypertension to avoid mislabelling as essential or gestational hypertension.

Suspected atypical haemolytic uraemic syndrome in two post-partum patients with foetal-death in utero responding to eculizumab.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is a rare condition with the triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury. Other conditions that present in a similar manner peri-partum include thrombotic thrombocytopaenic purpura, and pregnancy associated conditions including HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), severe pre-eclampsia and less commonly acute fatty liver of pregnancy. CASE REPORTS: We describe two cases of suspected aHUS, who presented post-partum with foetal death-in-utero at 33 and 37 weeks respectively. Both presented with the triad features of aHUS but had considerably different clinical courses. The first case required a prolonged ICU admission, needed intubation for neurological deterioration and dialysis for acute kidney injury, and developed complications including acute liver failure, septic shock, pancreatitis, and ischaemic colitis. Initial ADAMSTS13 activity was borderline-low (10.3%) and normal on repeat testing (42.6%), and there was no peri-partum pre-eclampsia. The other case remained clinically stable throughout her admission with creatinine peaking at 495, not requiring dialysis, minor liver transaminases derangement and was discharged after a week. Her ADAMSTS13 activity was normal (62%), and her pregnancy was complicated by peri-partum pre-eclampsia. Both eventually had a reduction in haemolysis with rapid and sustained reduction in LDH and normalised platelet counts, and complete recovery of renal function whilst receiving eculizumab therapy. CONCLUSIONS: It can be difficult to distinguish aHUS from other causes in peri-partum patients presenting with features of microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury, and often, aHUS can be precipitated by pregnancy. In the setting of the clinical urgency to treat aHUS early with eculizumab, this presents a diagnostic challenge, as confirmatory tests for aHUS are not immediately available.

Corticosteroids worsen proteinuria and increase intraglomerular signaling by NF-ĸB in a model of membranous glomerulonephritis.

BACKGROUND/AIMS: Passive Heymann nephritis (PHN) is a model of human membranous glomerulonephritis characterized by heavy proteinuria. We have recently demonstrated activation of NF-κB by podocytes in this model. In this study, therefore, we have determined whether dexamethasone (DEX) and pyrrolidine dithiocarbamate (PDTC), therapies that inhibit NF-κB, influence proteinuria. METHODS: Twenty-one days after induction of PHN, rats were divided into three groups: group 1 received saline, group 2 received DEX for 7 days, and group 3 received PDTC for 7 days. The effects of these drugs on activation of NF-κB and proteinuria were then determined. RESULTS: DEX administration was associated with a very significant increase in proteinuria, whereas PDTC produced a slight decrease. Within the glomerulus, both agents were associated with increased levels of IL-1ß mRNA and protein, compared with untreated rats, and there was increased nuclear localization of p50 in both of the treated groups. Neither agent, therefore, inhibited NF-κB activation within the glomerulus. Both agents produced a decrease in the systemic anti-sheep Ig immune response, and there was reduced interstitial αß T-cell infiltration compared with controls. CONCLUSION: These data suggest that agents predicted to inhibit NF-κB might have opposing effects in membranous glomerulonephritis. The use of steroids to treat membranous glomerulonephritis, therefore, might produce unpredictable results, depending on whether suppression of the systemic immune response or inflammatory events within the kidney is more important in a particular patient.

A pilot, randomized, double-blind, cross-over study of high cut-off versus high-flux dialysis membranes.

BACKGROUND: High cut-off (HCO) membranes may increase beta(2)-microglobulin (beta2M) removal compared to standard high-flux membranes. METHODS: Eight stable haemodialysis patients were enrolled in a prospective, randomized, double-blind, cross-over study and treated with HCO and high-flux membranes for 2 weeks each, between a 1-week washout period. Primary end point was serum beta2M removal. Secondary end points included serum albumin concentrations, albumin and small solute clearances. RESULTS: HCO membranes achieved significantly lower median post-dialysis beta2M concentration (10.8 vs. 14.2 mg/l; p = 0.003) and greater beta2M reduction ratio (62.3 vs. 51.0%; p < 0.002). Serum albumin decreased with HCO membranes (from 36 to 29.5 g/l; p = 0.018) but increased to 33.5 g/l after the washout period. Albumin clearance was significantly greater with HCO membranes (2.2 vs. 0.06 ml/min; p = 0.004). Urea reduction ratio was significantly lower with HCO membranes (64.8 vs. 71.5%; p < 0.001). CONCLUSION: beta2M removal was superior with HCO membranes. Reduction in serum albumin and lower small solute clearance require further investigations.

Induction of passive Heymann nephritis in complement component 6-deficient PVG rats.

Passive Heymann nephritis (PHN), a model of human membranous nephritis, is induced in susceptible rat strains by injection of heterologous antisera to rat renal tubular Ag extract. PHN is currently considered the archetypal complement-dependent form of nephritis, with the proteinuria resulting from sublytic glomerular epithelial cell injury induced by the complement membrane attack complex (MAC) of C5b-9. This study examined whether C6 and MAC are essential to the development of proteinuria in PHN by comparing the effect of injection of anti-Fx1A antisera into PVG rats deficient in C6 (PVG/C6(-)) and normal PVG rats (PVG/c). PVG/c and PVG/C6(-) rats developed similar levels of proteinuria at 3, 7, 14, and 28 days following injection of antisera. Isolated whole glomeruli showed similar deposition of rat Ig and C3 staining in PVG/c and PVG/C6(-) rats. C9 deposition was abundant in PVG/c but was not detected in PVG/C6(-) glomeruli, indicating C5b-9/MAC had not formed in PVG/C6(-) rats. There was also no difference in the glomerular cellular infiltrate of T cells and macrophages nor the size of glomerular basement membrane deposits measured on electron micrographs. To examine whether T cells effect injury, rats were depleted of CD8+ T cells which did not affect proteinuria in the early heterologous phase but prevented the increase in proteinuria associated with the later autologous phase. These studies showed proteinuria in PHN occurs without MAC and that other mechanisms, such as immune complex size, early complement components, CD4+ and CD8+ T cells, disrupt glomerular integrity and lead to proteinuria.

Targeting gene expression to endothelium in transgenic animals: a comparison of the human ICAM-2, PECAM-1 and endoglin promoters.

It is highly likely that successful pig-to-human xenotransplantation of vascularized organs will require genetic modification of the donor pig, and in particular of donor vascular endothelium. Promoters are generally tested in transgenic mice before generating transgenic pigs. Several promoters have been used to drive endothelial cell-specific expression in mice but none have yet been tested in pigs. We compared the promoters of three human genes that are predominantly expressed in vascular endothelium: intercellular adhesion molecule 2 (ICAM-2), platelet endothelial cell adhesion molecule 1 (PECAM-1) and endoglin. Expression of human complement regulatory proteins (hCRPs), directed by each of the promoters in mice, was largely restricted to vascular endothelium and leukocyte subpopulations. However, expression from the PECAM-1 promoter was weak in liver and non-uniform in the small vessels of heart, kidney, and lung. Conversely, expression from the endoglin promoter was consistently strong in the small vessels of these organs but was absent in larger vessels. The ICAM-2 promoter, which produced strong and uniform endothelial expression in all organs examined, was therefore used to generate hCRP transgenic pigs. Leukocytes from 57 pigs containing at least one intact transgene were tested for transgene expression by flow cytometry. Forty-seven of these transgenic pigs were further analyzed by immunohistochemical staining of liver biopsies, and 18 by staining of heart and kidney sections. Only two of the pigs showed expression, which appeared to be restricted to vascular endothelium in heart and kidney but was markedly weaker than in transgenic mice produced with the same batch of DNA. Thus, in this case, promoter performance in mice and pigs was not equivalent. The weak expression driven by the human ICAM-2 promoter in pigs relative to mice suggests the need for additional regulatory elements to achieve species-specific gene expression in pigs.

Renal ischemia-reperfusion increases endothelial VEGFR-2 without increasing VEGF or VEGFR-1 expression.

BACKGROUND: Hypoxia is a potent stimulus to angiogenesis. Expression of the angiogenic growth factor vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2) is up-regulated by hypoxia in a variety of organs and cell lines. We have previously reported that VEGF expression is not increased in renal ischemia-reperfusion injury, although tubular cells concentrate VEGF at their basolateral surface. In this study we assess whether altered VEGF receptor expression compensates for the lack of VEGF regulation during renal ischemia-reperfusion injury. METHODS: VEGFR-1 mRNA expression was assessed by Northern blotting and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). VEGFR-2 mRNA expression was analyzed by Northern blotting and in situ hybridization (ISH), while VEGFR-2 protein expression was studied using immunohistochemistry. VEGF mRNA expression was assessed by ISH. RESULTS: VEGFR-2 mRNA and protein expression were up-regulated without an increase in VEGF or VEGFR-1 expression. Normal kidneys showed low-level VEGFR-2 mRNA and protein expression in glomerular and peritubular endothelium. Following ischemia and ischemia-reperfusion, a marked increase in VEGFR-2 mRNA and protein expression was seen (2- to 4-fold). Most prominent was VEGFR-2 mRNA up-regulation in the glomerulus although, surprisingly, increased protein was not demonstrated here. ISH showed that VEGF mRNA was not up-regulated in this model, confirming our previous findings for VEGF. CONCLUSION: VEGF and VEGFR-1 expression are not increased by renal ischemia and ischemia-reperfusion injury. Instead, endothelial expression of VEGFR-2 is increased. VEGFR-2 up-regulation in renal ischemia-reperfusion may be important in mediating the mitogenic and anti-apoptotic actions of VEGF on endothelial cells, thereby preserving the integrity of the endothelium and the potential for blood supply to ischemic tissues.