Randomized, Controlled Trial of Tacrolimus and Prednisolone Monotherapy for Adults with De Novo Minimal Change Disease: A Multicenter, Randomized, Controlled Trial.

BACKGROUND AND OBJECTIVES: Minimal change disease is an important cause of nephrotic syndrome in adults. Corticosteroids are first-line therapy for minimal change disease, but a prolonged course of treatment is often required and relapse rates are high. Patients with minimal change disease are therefore often exposed to high cumulative corticosteroid doses and are at risk of associated adverse effects. This study investigated whether tacrolimus monotherapy without corticosteroids would be effective for the treatment of de novo minimal change disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a multicenter, prospective, open-label, randomized, controlled trial involving six nephrology units across the United Kingdom. Adult patients with first presentation of minimal change disease and nephrotic syndrome were randomized to treatment with either oral tacrolimus at 0.05 mg/kg twice daily, or prednisolone at 1 mg/kg daily up to 60 mg daily. The primary outcome was complete remission of nephrotic syndrome after 8 weeks of therapy. Secondary outcomes included remission of nephrotic syndrome at 16 and 26 weeks, rates of relapse of nephrotic syndrome, and changes from baseline kidney function. RESULTS: There were no significant differences between the tacrolimus and prednisolone treatment cohorts in the proportion of patients in complete remission at 8 weeks (21 out of 25 [84%] for prednisolone and 17 out of 25 [68%] for tacrolimus cohorts; P=0.32; difference in remission rates was 16%; 95% confidence interval [95% CI], -11% to 40%), 16 weeks (23 out of 25 [92%] for prednisolone and 19 out of 25 [76%] for tacrolimus cohorts; P=0.25; difference in remission rates was 16%; 95% CI, -8% to 38%), or 26 weeks (23 out of 25 [92%] for prednisolone and 22 out of 25 [88%] for tacrolimus cohorts; P=0.99; difference in remission rates was 4%; 95% CI, -17% to 25%). There was no significant difference in relapse rates (17 out of 23 [74%] for prednisolone and 16 out of 22 [73%] for tacrolimus cohorts) for patients in each group who achieved complete remission (P=0.99) or in the time from complete remission to relapse. CONCLUSIONS: Tacrolimus monotherapy can be effective alternative treatment for patients wishing to avoid steroid therapy for minimal change disease. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_01_16_CJN06180519.mp3.

Meningococcal B Vaccine Failure With a Penicillin-Resistant Strain in a Young Adult on Long-Term Eculizumab.

We describe a case of invasive meningococcal disease due to a vaccine-preventable and penicillin-resistant strain in a fully immunized young adult on long-term complement inhibitor therapy and daily penicillin chemoprophylaxis. Eculizumab is a humanized monoclonal antibody that binds human complement C5 protein and inhibits the terminal complement pathway. It is currently recommended for the treatment of complement-mediated thrombotic microangiopathies. An unwanted complication of inhibiting complement, however, is an increased risk of invasive meningococcal disease. Here, we report the first case of meningococcal group B vaccine failure in a young adult receiving eculizumab for atypical hemolytic uremic syndrome. She developed invasive meningococcal disease due to a vaccine-preventable and penicillin-resistant meningococcal group B strain 4 months after receiving 2 doses of meningococcal group B vaccine while on oral penicillin prophylaxis against meningococcal infection.

Rate of Decline of Kidney Function, Modality Choice, and Survival in Elderly Patients with Advanced Kidney Disease.

AIM: In elderly, dependent patients with advanced chronic kidney disease, dialysis may confer only a small survival advantage over conservative kidney management (CKM). We investigated the role of rate of decline of kidney function on treatment choices and survival. METHODS: We identified a retrospective (1995-2010) cohort of patients aged over 75 years, with progressive kidney impairment and an estimated glomerular filtration rate (eGFR) between 10 and 15 ml/min/1.73 m2. All subsequently chose to be treated by either dialysis or CKM. Patients were followed for a minimum of 3 years. RESULTS: Of 250 patients identified, 92 (37%) opted for dialysis and 158 (63%) for CKM. Mean age was 80.9 ± 4.0 years. eGFR was 13.3 ± 1.4 initially and 8.7 ± 3.0 ml/min/1.73 m2 at follow-up. Both were similar in those on dialysis and CKM pathways. Rate of decline of eGFR was more rapid in those choosing dialysis (0.45 (interquartile range, IQR 0.64) vs. 0.21 (IQR 0.28) ml/min/1.73 m2/month, p < 0.001), and independently predicted choice of CKM. In patients with high comorbidity, choice of dialysis was associated with a non-significant adjusted survival advantage of 5 months. Inclusion in models of time dependent eGFR during follow-up (eGFRtd) - a reflection of the rate of decline of kidney function - showed it to be independently associated with mortality risk in those on the CKM (p < 0.001) but not on the dialysis pathway. CKM pathway patients at the 25th centile of eGFRtd had an adjusted survival of 7 months compared to 63 months for those at the 75th centile. CONCLUSIONS: Rate of decline of kidney function is a determinant of CKM choice in elderly patients and is associated with mortality risk in patients of the CKM pathway. These findings should inform counselling.

Factors determining penetrance in familial atypical haemolytic uraemic syndrome.

BACKGROUND: Inherited abnormalities of complement are found in ∼60% of patients with atypical haemolytic uraemic syndrome (aHUS). Such abnormalities are not fully penetrant. In this study, we have estimated the penetrance of the disease in three families with a CFH mutation (c.3643C>G; p. Arg1215Gly) in whom a common lineage is probable. 25 individuals have been affected with aHUS with three peaks of incidence-early childhood (n=6), early adulthood (n=11) and late adulthood (n=8). Eighteen individuals who have not developed aHUS carry the mutation. METHODS: We estimated penetrance at the ages of 4, 27, 60 and 70 years as both a binary and a survival trait using MLINK and Mendel. We genotyped susceptibility factors in CFH, CD46 and CFHR1 in affected and unaffected carriers. RESULTS AND CONCLUSIONS: We found that the estimates of penetrance at the age of 4 years ranged from <0.01 to 0.10, at the age of 27 years from 0.16 to 0.29, at the age of 60 years from 0.39 to 0.51 and at the age of 70 years from 0.44 to 0.64. We found that the CFH haplotype on the allele not carrying the CFH mutation had a significant effect on disease penetrance. In this family, we did not find that the CD46 haplotypes had a significant effect on penetrance.

Survival of elderly patients with stage 5 CKD: comparison of conservative management and renal replacement therapy.

BACKGROUND: Elderly patients with end-stage renal disease and severe extra-renal comorbidity have a poor prognosis on renal replacement therapy (RRT) and may opt to be managed conservatively (CM). Information on the survival of patients on this mode of therapy is limited. METHODS: We studied survival in a large cohort of CM patients in comparison to patients who received RRT. RESULTS: Over an 18-year period, we studied 844 patients, 689 (82%) of whom had been treated by RRT and 155 (18%) were CM. CM patients were older and a greater proportion had high comorbidity. Median survival from entry into stage 5 chronic kidney disease was less in CM than in RRT (21.2 vs 67.1 months: P < 0.001). However, in patients aged > 75 years when corrected for age, high comorbidity and diabetes, the survival advantage from RRT was ~ 4 months, which was not statistically significant. Increasing age, the presence of high comorbidity and the presence of diabetes were independent determinants of poorer survival in RRT patients. In CM patients, however, age > 75 years and female gender independently predicted better survival. CONCLUSIONS: In patients aged > 75 years with high extra-renal comorbidity, the survival advantage conferred by RRT over CM is likely to be small. Age > 75 years and female gender predicted better survival in CM patients. The reasons for this are unclear.

Successful stabilisation of nephropathy in a patient with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-band, skin changes) syndrome on treatment with mycophenolate and steroids: a case report.

INTRODUCTION: Renal involvement in POEMS (polyneuropathy, organomegaly, endocrinopathy, M-band, skin changes) syndrome is considered to be an under-diagnosed phenomenon with no clear treatment path. The limited literature suggests steroids to be the drug of choice, although improvements are limited and usually reverse on withdrawal of the drug. CASE PRESENTATION: A 52-year-old Caucasian woman presenting with features consistent with POEMS syndrome developed progressive renal impairment with proteinuria. Renal biopsy revealed a membranoproliferative glomerulonephritis. She was treated with relatively low dose oral mycophenolate mofetil and prednisolone which stabilised her nephropathy and neuropathy. CONCLUSION: We describe an alternative therapeutic option in patients with this serious but poorly understood condition.

Superior vena cava obstruction presenting with epistaxis, haemoptysis and gastro-intestinal haemorrhage in two men receiving haemodialysis with central venous catheters: two case reports.

INTRODUCTION: Superior vena cava (SVC) obstruction secondary to central venous catheterization is an increasingly recognized complication. CASE PRESENTATION: We present two cases of superior vena cava obstruction secondary to indwelling central venous catheters used for haemodialysis access. One of the patients developed the unusual complications of torrential epistaxis and haemoptysis, which has been reported only once so far in the literature. The other patient developed melaena secondary to downhill oesophageal varices. We briefly discuss the pathophysiology, symptoms and signs, investigations and management of superior vena cava obstruction and thrombosis. CONCLUSION: Increasing use of central venous access for haemodialysis will increase the incidence of central venous stenosis, thrombosis and exhaustion. Superior vena cava obstruction is likely to be an increasingly recognised complication of vascular access in the future.

Infective spondylodiscitis in patients on high-flux hemodialysis and on-line hemodiafiltration.

Infective spondylodiscitis (ISD) is a rare but potentially devastating condition in hemodialysis (HD) patients. Reports are limited especially in patients receiving high-flux HD and hemodiafiltration (HDF). In a retrospective analysis, 13 patients on our maintenance high-flux HD/HDF program were identified as having has infective spondylodiscitis over a 10-year period (1997-2006), an incidence of approximately 1 episode every 215 patient-years. The incidence was around 3 times higher in patients dialyzing with tunnelled central venous catheters (TCVC) than in those with arteriovenous fistulae. Affected patients were elderly (mean age 70 years) and had multiple comorbidities. Access problems, particularly TCVC infection, were common in the months preceding it's onset. Tunnelled central venous catheter removal during these episodes did not necessarily prevent it. Diagnosis was based on a history of back pain, raised C-reactive protein, positive blood cultures, and characteristic magnetic resonance findings. Many patients were apyrexial and had normal white cell counts. In our patients on high-flux HD/hemodiafiltration, its incidence appears comparable to that in conventional HD settings. No patients had infection with waterborne organisms. Blood cultures were positive in 77%. Gram-positive organisms predominated, particularly Staphylococcus aureus. The major route of infection was hematogenous, with the most likely source the venous access. All received antibiotics for 6 to 12 weeks or until death. Only 2 patients underwent surgical drainage. Mortality was high (46%) and predicted by the development of complications, and by pre-existing cardiovascular comorbidity. Prevention, using strategies to reduce the prevalence of bacteremia, including limiting the use of TCVC, should be an overriding aim.

Familial membranous nephropathy: an X-linked genetic susceptibility?

BACKGROUND: Membranous nephropathy (MN) is the most common histological diagnosis in adults with nephrotic syndrome and a leading cause of end-stage kidney failure from glomerulonephritis. Little is known about the underlying aetiology, although anti-glomerular antibodies have been implicated. No specific underlying genetic defect has yet been identified. METHODS: In a family with four members in three generations affected by primary MN, the serum of affected members and their mothers were assessed for anti-glomerular antibodies. RESULTS: All four affected are male and connected through the maternal line, indicative of X-linked inheritance. Age of onset of nephrotic syndrome varied between 1 and 67 years of age, suggesting that a potential underlying gene may confer a genetic predisposition to MN, but other factors, genetic or environmental, are necessary to trigger the disease. Serologic studies revealed antibodies against glomerular and peritubular endothelial cells in the mother of the youngest patient. CONCLUSIONS: We have identified the largest reported family with a potential X-linked susceptibility to MN. Foeto-maternal alloimmunization may have triggered the disease in the youngest individual. Considering that the majority of patients with sporadic MN are male, identification of an X-linked predisposing factor may have implications well beyond this family and could provide a target for treatment.

Factors affecting long-term survival of tunnelled haemodialysis catheters--a prospective audit of 812 tunnelled catheters.

BACKGROUND: In 2001, in the US, 23% of haemodialysis patients were dialysing through tunnelled venous catheters (TVCs), and in the UK (2006) there were 28% of prevalent patients using catheters. It is unlikely that numbers will significantly decrease. We present the results of a prospective audit of the survival of 812 TVCs placed in 492 patients at our institution over a 6-year period (comprising 212 048 patient catheter days or 7068 patient catheter months of follow-up). Four different designs of catheter were studied: Split-Cath III (Medcomp), HemoSplit (Bard), Tesio twin catheter (Medcomp) and Permcath (Quinton). METHODS: We used Kaplan-Meier survival analysis with log-rank test, to compare the effect of different parameters on catheter survival. The relative importance of significant parameters was determined by Cox regression analysis. RESULTS: We have shown a significant catheter survival advantage of first catheters over second and subsequent insertions, of right internal jugular site over left internal jugular and thereafter over femoral site, and of non-diabetic over diabetic patients. Patient age, sex and operator (physician in ward-based procedure room under ultrasound control or surgeon in operating theatre under fluoroscopic assistance) did not significantly affect survival. The Permcath design demonstrated inferior survival in all but first catheter insertions in catheter-naïve patients. The HemoSplit and Tesio twin catheter designs demonstrated best survival overall. By Cox proportional hazard modelling the design and the position of the TVC seemed to be the most significant independent survival factors. CONCLUSIONS: Clinicians need accurate data regarding catheter survival, mode of insertion and design, to inform practice.

Atypical haemolytic uraemic syndrome associated with a hybrid complement gene.

BACKGROUND: Sequence analysis of the regulators of complement activation (RCA) cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH) and the genes for the five factor H-related proteins (CFHL1-5; aliases CFHR1-5). CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS). The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS. METHODS AND FINDINGS: In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1-21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A) that has been previously described in association with aHUS. CONCLUSIONS: CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene.

Choosing not to dialyse: evaluation of planned non-dialytic management in a cohort of patients with end-stage renal failure.

OBJECTIVES: To study factors influencing the recommendation for palliative (non-dialytic) treatment in patients approaching end-stage renal failure and to study the subsequent outcome in patients choosing not to dialyse. DESIGN: Cohort study of patients approaching end-stage renal failure who underwent multidisciplinary assessment and counselling about treatment options. Recruitment was over 54 months, and follow-up ranged from 3 to 57 months. Groups were defined on the basis of the therapy option recommended (palliative or renal replacement therapy). SETTING: Renal unit in a district general hospital serving a population of about 1.15 million people. SUBJECTS: 321 patients, mean age +/- SD 61.5 +/- 15.4 years (range: 16-92), 57% male, 30% diabetic. MAIN OUTCOME MEASURES: Survival, place of death (hospital or community). RESULTS: Renal replacement therapy was recommended in 258 patients and palliative therapy in 63 (19.6%). By logistic regression analysis, patients recommended for palliative therapy were more functionally impaired (modified Karnofsky scale), older and more likely to have diabetes. The comorbidity severity score was not an independent predictor. Thirty-four patients eventually died during palliative treatment, 26 of whom died of renal failure. Ten patients recommended for palliative treatment opted for and were treated by dialysis. Median survival after dialysis initiation in these patients (8.3 months) was not significantly longer than survival beyond the putative date of dialysis initiation in palliatively treated patients (6.3 months). 65% of deaths occurring in dialysed patients took place in hospital compared with 27% in palliatively treated patients (p = 0.001). CONCLUSIONS: In high-risk, highly dependent patients with renal failure, the decision to dialyse or not has little impact on survival. Dialysis in such patients risks unnecessary medicalisation of death.

Spinal cord infarction following central-line insertion.

Hemothorax is a recognized complication of central line insertion into the jugular or subclavian vein. We describe a case of hemothorax consequent upon acute dialysis catheter insertion, which resulted in spinal cord infarction and quadriplegia. We postulate that the extensive mediastinal shift induced after insertion of the catheter resulted in stretching of the veins draining the cord with a resultant drop in perfusion pressure and infarction. This case highlights a hitherto unreported complication of this procedure.