Monogenic causes of chronic kidney disease in adults.

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.

Clinical and pathologic characteristics of hereditary apolipoprotein A-I amyloidosis in Ireland.

AIM: Apolipoprotein A-I amyloidosis is a rare, autosomal dominant disorder characterized by progressive accumulation of amyloid fibrils in tissues, leading to renal and hepatic disease. We describe the clinical manifestations and pathologic features of kidney disease in three Irish families. METHODS: This observational study examines all known cases of chronic kidney disease due to hereditary apolipoprotein A-I amyloidosis in Ireland. Patients were identified by physician interview. In all of the affected individuals the disease was caused by the Gly26Arg heterozygous mutation. Immunohistochemistry confirmed that amyloid deposits were composed of apolipoprotein A-I fibrils. Family trees and clinical data were obtained via analysis of patient medical records. RESULTS: The vast majority of affected cases had demonstrable kidney disease, with variable liver disease. Renal disease most commonly manifested as slowly progressive renal impairment with mild proteinuria. In one kindred, a severe, debilitating peripheral neuropathy was common among affected family members. Histology demonstrated tubulointerstitial fibrosis with amyloid deposition in the medulla. There was very high penetrance within affected families. Of five patients who were transplanted, one transplant was lost after 5 years due to recurrent disease. One patient died from sepsis shortly after transplant. CONCLUSION: Hereditary apolipoprotein A-I amyloidosis is characterized by slowly progressive renal disease. Amyloid is deposited in the renal medulla highlighting the need to examine the medulla on renal biopsy. Overall, kidney transplantation conferred a survival advantage.

Severe rhabdomyolysis as a consequence of the interaction of fusidic acid and atorvastatin.

Rhabdomyolysis is a known complication of statin therapy and may be triggered by a pharmacokinetic interaction between a statin and a second medication. Fatal statin-induced rhabdomyolysis has an incidence of 0.15 deaths/million prescriptions. We describe 4 cases of severe rhabdomyolysis with the common feature of atorvastatin use and coadministration of fusidic acid. All cases involved long-term therapy with atorvastatin; fusidic acid was introduced for treatment of osteomyelitis or septic arthritis. Three cases occurred in the setting of diabetes mellitus, with 2 in patients with end-stage renal disease, suggesting increased susceptibility to atorvastatin-fusidic acid-induced rhabdomyolysis in these patient populations. Of the 4 patients in this series, 3 died. Fusidic acid is a unique bacteriostatic antimicrobial agent with principal antistaphylococcal activity. There have been isolated reports of rhabdomyolysis attributed to the interaction of statins and fusidic acid, the cause of which is unclear. Fusidic acid does not inhibit the cytochrome P450 3A4 isoenzyme responsible for atorvastatin metabolism; increased atorvastatin levels due to inhibition of the glucuronidation pathway may be responsible. Considering the low frequency of fusidic acid use, the appearance of 4 such cases within a short time and in a small population suggests the probability that development of this potentially fatal complication may be relatively high.

Cinacalcet and achievement of the NKF/K-DOQI recommended target values for bone and mineral metabolism in real-world clinical practice--the ECHO observational study.

BACKGROUND: The use and effectiveness of cinacalcet in 'real-world' clinical practice was investigated in a pan-European observational study in dialysis patients with secondary hyperparathyroidism (SHPT) of varying severity. METHODS: Adult patients with chronic kidney disease on dialysis who had initiated cinacalcet treatment were enrolled. Data were collected 6 months before initiating cinacalcet, at baseline (initiation of cinacalcet) and up to 12 months after cinacalcet initiation. RESULTS: A total of 1865 patients [mean (SD) age 58 (15) years] were enrolled from 187 sites in 12 countries. Most patients had a dialysis vintage of > or =1 year (1-5 years, n = 833; >5 years, n = 748 versus <1 year, n = 265). The patients generally had severely uncontrolled intact parathyroid hormone (iPTH) serum levels (median 721 pg/ml) and elevated phosphorus (median 5.9 mg/dl) and calcium (median 9.6 mg/dl) at baseline, despite being prescribed conventional therapies. The proportions of patients achieving the recommended [NKF-K/DOQI(TM) (KDOQI(TM))] targets increased from baseline [4%, 39%, 40% and 46% for iPTH, phosphorus, calcium and calcium-phosphorus product (Ca x P), respectively] to Month 12 (28%, 48%, 51% and 68%, respectively). At Month 12, 18% of patients had achieved the combined target for iPTH + Ca x P compared with 2% at baseline. Most patients (65%) received <60 mg/day cinacalcet at Month 12. Vitamin D sterol use remained fairly stable throughout the study. There was a 13% decrease in prescribed sevelamer; use of calcium-based phosphate binders increased by 5.6%. There was no unexpected safety or tolerability concerns. CONCLUSION: This analysis of current European clinical practice shows that-consistent with findings from randomized controlled trials and retrospective observational studies-cinacalcet improves attainment of KDOQI bone metabolism targets in dialysis patients with various stages of SHPT.

Granulomatous interstitial nephritis secondary to adalimumab therapy.

Tumour necrosis factor α (TNF-α) inhibitors are frequently used for the treatment of immune-mediated diseases. Conversely, cytokine therapy has the potential to paradoxically induce autoimmunity. A number of case reports have emerged concerning sarcoid-like granulomatosis secondary to TNF-α therapy, an adverse effect that typically affects the pulmonary and cutaneous systems. Granulomatous interstitial nephritis (GIN) is a relatively unknown, relatively under-reported consequence of adalimumab therapy that can have important clinical implications. To our knowledge, this is the first case report of GIN secondary to anti-TNF-α therapy necessitating a prolonged period of dialysis and the first report demonstrating the successful use of secukinumab as an alternative immunomodulatory agent.

Endocrine abnormalities in chronic renal failure.

Much needs to be achieved in improving survival and quality of life for chronic renal failure patients. Progress in attaining this goal may accrue from attention to underlying pathophysiologic processes early and throughout a person's life. The endocrine perturbations described in this article--alterations in the homeostasis of phosphorus, calcium, vitamin D and parathyroid hormone; erythropoietin deficiency; and sexual dysfunction in uremia--provide good examples for the need to identify early and manage prospectively over time manifestations of chronic renal failure. The complexity of the skeletal and extraskeletal sequelae of dysregulated mineral metabolism and the complications of chronic anemia have been discussed, while stressing possible implications of these endocrine abnormalities for both morbidity and mortality. There is a great need for more randomized clinical trials to evaluate new and old treatment approaches, with the goal of developing better evidence-based practice guidelines.

Vascular access outcomes using the transposed basilic vein arteriovenous fistula.

BACKGROUND: Although the transposed basilic vein arteriovenous fistula (TBAVF) is increasingly performed for hemodialysis vascular access in patients lacking adequate superficial veins, little is known about the long-term patency or risk factors for failure. METHODS: A retrospective analysis was conducted for 99 patients who had a TBAVF created between April 1997 and October 2001. Primary outcomes were unassisted and assisted patency rates and primary failure rates. RESULTS: This was the first access procedure in 46% of patients, mean age was 55 years, and 46% were men. Unassisted and assisted patency rates were 47% and 64% at 1 year and 41% and 58% at 2 years, respectively. Primary access failure occurred in 23% of cases. Unassisted access patency was significantly worse in patients with a previous access (relative risk [RR], 2.04; confidence interval [CI], 1.09 to 3.85; P = 0.03) or an ipsilateral central venous catheter (RR, 2.92; CI, 1.34 to 6.38; P < 0.01). Primary access failure was affected by older age (RR, 2.0; CI, 1.20 to 3.38; P < 0.01), obesity (RR, 7.1; CI, 1.65 to 30.1; P < 0.05), and a previous vascular access (RR, 6.4; CI, 1.49 to 27.6; P = 0.01). Steal syndrome requiring intervention occurred in 5% of cases. CONCLUSION: In summary, the TBAVF provides a viable option for vascular access; however, certain patient characteristics seem to affect long-term patency and should be considered when exploring access options.

Predicting the outcome of renal replacement therapy in severe acute renal failure.

Continuous renal replacement therapy (CRRT), such as continuous venovenous hemofiltration, has theoretical advantages over intermittent hemodialysis (IHD) that are related to cardiorespiratory stability, metabolic control, and fluid balance allowing nutritional supplementation. However, retrospective and controlled studies fail to show these advantages because of comorbidity associated with triage to CRRT. To compare outcomes using IHD versus CRRT, we applied published risk stratification models (Cleveland Clinic Foundation, Lohr index, and APACHE II) to the 349 patients with acute renal failure requiring renal replacement therapy at University of Michigan over the 2 year period including 1995 and 1996. The Cleveland Clinic Foundation model best predicted overall mortality, but our CRRT patients had excess, unpredicted mortality that was particularly prominent in the lower risk categories. The Lohr clinical score predicted mortality less accurately but also was associated with higher, unpredicted mortality at lower risk scores among the CRRT patients. APACHE II scores did not predict mortality very well among IHD, CRRT, or the combined group of patients. We conclude that the need for CRRT itself predicts mortality over and above that included in published risk models. Either CRRT is associated with some unidentified morbidity (e.g., treatment associated infection) or, more likely, triage to CRRT is associated with as yet unspecified comorbidity not detected in existing risk stratification schemes. It will be important to address these issues in any future studies evaluating outcome or comparing renal replacement therapy modalities among patients with severe acute renal failure.

Early readmission and length of hospitalization practices in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Rising hospital care costs have created pressure to shorten hospital stays and emphasize outpatient care. This study tests the hypothesis that shorter median length of stay (LOS) as a dialysis facility practice is associated with higher rates of early readmission. METHODS: Readmission within 30 days of each hospitalization was evaluated for participants in the Dialysis Outcomes and Practice Patterns Study, an observational study of randomly selected hemodialysis patients in the United States (142 facilities, 5095 patients with hospitalizations), five European countries (101 facilities, 2281 patients with hospitalizations), and Japan (58 facilities, 883 patients with hospitalizations). Associations between median facility LOS (estimated from all hospitalizations at the facility and interpreted as a dialysis facility practice pattern) and odds of readmission were assessed using logistic regression, adjusted for patient characteristics and the LOS of each index hospitalization. RESULTS: Risk of readmission was directly and significantly associated with LOS of the index hospitalization (adjusted odds ratio [AOR] 1.005 per day in median facility LOS, p = 0.007) and inversely associated with median facility LOS (AOR = 0.974 per day, p = 0.016). This latter association was strongest for US hemodialysis centers (AOR = 0.954 per day, p = 0.015). CONCLUSIONS: Dialysis facilities with shorter median hospital LOS for their patients have higher odds of readmission, particularly in the United States, where there is greater pressure to shorten LOS. The determinants and consequences of practices related to hospital LOS for hemodialysis patients should be further studied.

Outpatient High-Dose Urokinase Infusion Improves Dialysis Catheter Longevity: A Prospective Observational Study.

Catheter thrombosis is a major limiting factor affecting catheter survival in hemodialysis (HD). A previous retrospective study highlighted the utility of outpatient intradialytic high-dose urokinase (HDU) infusion in the treatment of HD catheter thrombosis. The present study was designed to prospectively evaluate the effectiveness of 250 000 IU urokinase given as a 3-hour infusion during HD. The infusion would follow detection of a drop in blood flow thought to be secondary to thrombosis [a "thrombotic event" (TE)] after exclusion of nonthrombotic causes of drop in blood flow [a "nonthrombotic event" (NTE)], such as systemic hypotension or suboptimal position of the catheter on x ray. An "event" was defined as a drop in pump blood flow by greater than or equal to 20% of the prescribed blood flow. Twenty patients (mean age 57.7 years; 13 males) with documented or potentially long-term catheters were recruited (total catheters used, 30) from an outpatient HD unit. A variety of catheter types were used. Catheter position was confirmed on x ray. Hemodialysis sessions were monitored for 6 months or until catheter removal (whichever was earlier). Thrombotic and NTEs (mostly related to drop in blood flow) were noted. The use of intradialytic HDU infusions was monitored. Improvement was defined as reestablishment of blood flow to within 10% of prescription. There were 24 TEs in 11 patients and 15 NTEs in 7 patients. Twenty-one of 22 (95%) TEs responded to HDU, with complete restoration of blood flow; in 1/22 HDU-treated instances there was a partial response. For 2/24 TEs the patients underwent catheter stripping with good results. Twelve of 15 NTEs occurred in the first 2 weeks of catheter placement versus 6/24 TEs (p = 0.001, chi-square). Catheter survival was longer than 24 weeks in 12/30 catheters. Nine catheters were lost to NTEs. No catheter was lost secondary to a TE. It is therefore concluded that intradialytic outpatient HDU is useful for the treatment of HD catheter thrombosis. It may obviate/reduce the need for catheter stripping or replacement. Randomized controlled trials with this approach are needed. A higher proportion of NTEs tended to occur earlier after catheter placement compared to TEs.

Effect of time on sensitivity and specificity of access flow in predicting thrombosis.

Dialysis access monitoring may help decrease thrombosis-related morbidity. We investigated the effect of time elapsed since an access flow measurement on test accuracy of a novel flow monitoring method called variable flow (VF) Doppler. A retrospective review was conducted in 36 patients with prosthetic grafts for vascular access using access thrombosis as the clinical endpoint. Receiver operator characteristic (ROC) curves and test sensitivity and specificity were determined for various follow-up time intervals. ROC analysis showed increasing test discrimination for shorter time intervals. Sensitivity and specificity for a commonly used surveillance threshold (600 ml/min) showed specificity that was little changed (88-93%) from follow-up time intervals of 15 days to 6 months. However, sensitivity was low (21%) at 6 months, increased to 50% at 2 months, 67% at 1 month, and 100% at 15 days (a single event). Low access blood flow using VF Doppler predicts near-term thrombosis. These data further imply that the discriminative value of access flow monitoring appears to be highly dependent on time from the flow measurement, improving with shorter time intervals from the measurement.