Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit.

Acute normocapnic hypoxemia can cause functional renal insufficiency by increasing renal vascular resistance (RVR), leading to renal hypoperfusion and decreased glomerular filtration rate (GFR). Insulin-like growth factor 1 (IGF-1) activity is low in fetuses and newborns and further decreases during hypoxia. IGF-1 administration to humans and adult animals induces pre- and postglomerular vasodilation, thereby increasing GFR and renal blood flow (RBF). A potential protective effect of IGF-1 on renal function was evaluated in newborn rabbits with hypoxemia-induced renal insufficiency. Renal function and hemodynamic parameters were assessed in 17 anesthetized and mechanically ventilated newborn rabbits. After hypoxemia stabilization, saline solution (time control) or IGF-1 (1 mg/kg) was given as an intravenous (i.v.) bolus, and renal function was determined for six 30-min periods. Normocapnic hypoxemia significantly increased RVR (+16%), leading to decreased GFR (-14%), RBF (-19%) and diuresis (-12%), with an increased filtration fraction (FF). Saline solution resulted in a worsening of parameters affected by hypoxemia. Contrarily, although mean blood pressure decreased slightly but significantly, IGF-1 prevented a further increase in RVR, with subsequent improvement of GFR, RBF and diuresis. FF indicated relative postglomerular vasodilation. Although hypoxemia-induced acute renal failure was not completely prevented, IGF-1 elicited efferent vasodilation, thereby precluding a further decline in renal function.

ESRD caused by nephrolithiasis: prevalence, mechanisms, and prevention.

BACKGROUND: The contribution of nephrolithiasis-related end-stage renal disease (ESRD) to patients requiring renal replacement therapy has never been specifically evaluated. METHODS: Of the entire cohort of 1,391 consecutive patients who started maintenance dialysis therapy at our nephrology department between January 1989 and December 2000, a total of 45 patients (21 men) had renal stone disease as the cause of ESRD and constitute the study material. Type and cause of renal stone disease was determined in the 45 patients, as well as the change in prevalence of nephrolithiasis-related ESRD with time during this 12-year period. RESULTS: The overall proportion of nephrolithiasis-related ESRD was 3.2%. Infection (struvite) stones accounted for 42.2%; calcium stones, 26.7%; uric acid nephrolithiasis, 17.8%; and hereditary diseases (including primary hyperoxaluria type 1 and cystinuria), 13.3% of cases. Women were predominant among patients with infection and calcium stones, whereas men were predominant among patients with uric acid or hereditary stone disease. The proportion of patients with nephrolithiasis-related ESRD decreased from 4.7% in the triennial period 1989 to 1991 to 2.2% in the most recent period, 1998 to 2000 ( P = 0.07). This tendency to a decreasing prevalence mainly was caused by a rarefaction of infection and calcium stones with time, whereas frequencies of uric acid and hereditary stone disease remained essentially unchanged. CONCLUSION: Severe forms of nephrolithiasis remain an underestimated cause of potentially avoidable ESRD and need for renal replacement therapy. These findings highlight the crucial importance of accurate stone analysis and metabolic evaluation to provide early diagnosis and proper therapy for conditions that may lead to ESRD through recurrent stone formation and/or parenchymal crystal infiltration.

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit.

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.

Microalbuminuria and hyperfiltration in subjects with nephro-urological disorders.

BACKGROUND: Microalbuminuria (MA) has been shown to be an early biomarker of renal damage. It is postulated that MA is the early result of hyperfiltration, which could evolve into glomerular sclerosis and renal failure if hyperfiltration is left untreated. We hypothesized that MA is a good indicator of hyperfiltration in children with kidney disorders, obviating the need to calculate the filtration fraction (FF). METHODS: A total of 155 children or young adults were prospectively included [42 single kidney (SK), 61 vesico-ureteral reflux, 23 obstructive uropathies, 29 other kidney diseases]. We measured inulin, para-aminohippuric acid clearances, FF and MA. Prediction of hyperfiltration was explored by studying the association between the FF and other variables such as urinary albumin (Alb), urinary albumin-creatinine ratio (ACR) and creatinine clearance. RESULTS: A significant but weak association between urinary Alb or ACR and FF was found in subjects with an SK (Spearman correlation coefficients 0.32 and 0.19, respectively). Multivariate analysis also showed that urinary Alb and ACR significantly predict FF only in subjects with an SK (r(2) = 0.17, P = 0.01 and r(2) = 0.13, P = 0.02, respectively). This holds true only in subjects with an SK and inulin clearance >90 mL/min/1.73 m(2) (r(2) = 0.41, P < 0.001). There was no association between creatinine clearance and FF. CONCLUSIONS: MA is not associated with FF in our subjects with nephro-urological disorders, except in those with an SK, where the association is weak, indicating that MA is due to other mechanisms than high FF and cannot predict hyperfiltration in such groups.

Initial and Extended Use of Femoral Versus Nonfemoral Double-Lumen Vascular Catheters and Catheter-Related Infection During Continuous Renal Replacement Therapy.

BACKGROUND: The risk of catheter-related infection or bacteremia, with initial and extended use of femoral versus nonfemoral sites for double-lumen vascular catheters (DLVCs) during continuous renal replacement therapy (CRRT), is unclear. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: Critically ill patients on CRRT in a combined intensive care unit of a tertiary institution. FACTOR: Femoral versus nonfemoral venous DLVC placement. OUTCOMES: Catheter-related colonization (CRCOL) and bloodstream infection (CRBSI). MEASUREMENTS: CRCOL/CRBSI rates expressed per 1,000 catheter-days. RESULTS: We studied 458 patients (median age, 65 years; 60% males) and 647 DLVCs. Of 405 single-site only DLVC users, 82% versus 18% received exclusively 419 femoral versus 82 jugular or subclavian DLVCs, respectively. The corresponding DLVC indwelling duration was 6±4 versus 7±5 days (P=0.03). Corresponding CRCOL and CRBSI rates (per 1,000 catheter-days) were 9.7 versus 8.8 events (P=0.8) and 1.2 versus 3.5 events (P=0.3), respectively. Overall, 96 patients with extended CRRT received femoral-site insertion first with subsequent site change, including 53 femoral guidewire exchanges, 53 new femoral venipunctures, and 47 new jugular/subclavian sites. CRCOL and CRBSI rates were similar for all such approaches (P=0.7 and P=0.9, respectively). On multivariate analysis, CRCOL risk was higher in patients older than 65 years and weighing >90kg (ORs of 2.1 and 2.2, respectively; P<0.05). This association between higher weight and greater CRCOL risk was significant for femoral DLVCs, but not for nonfemoral sites. Other covariates, including initial or specific DLVC site, guidewire exchange versus new venipuncture, and primary versus secondary DLVC placement, did not significantly affect CRCOL rates. LIMITATIONS: Nonrandomized retrospective design and single-center evaluation. CONCLUSIONS: CRCOL and CRBSI rates in patients on CRRT are low and not influenced significantly by initial or serial femoral catheterizations with guidewire exchange or new venipuncture. CRCOL risk is higher in older and heavier patients, the latter especially so with femoral sites.

Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

Early intensification and autologous stem cell transplantation in patients with systemic AL amyloidosis: a single-centre experience.

Primary systemic amyloidosis (AL amyloidosis) continues to have a very poor prognosis. Most therapeutic strategies remain unsatisfactory. Conventional chemotherapy is known to offer at best only moderate efficacy. Several studies have yielded higher complete response rates after high-dose chemotherapy and autologous stem cell transplantation (ASCT) in addition to improving outcomes in a subgroup of patients. However, the superiority of an intensive approach in AL amyloidosis has not been confirmed in a randomised trial. The precise role of ASCT remains unclear. We report our experience in 16 patients diagnosed with AL amyloidosis and treated in a multidisciplinary approach with high-dose melphalan and ASCT. Median age was 59 (39-71) years. The kidneys were predominantly affected in 75% of cases; two or more organs were affected in 38%. Median time from diagnosis to transplantation was 2 (1-4) months. Three patients (19%) developed acute renal failure and required transient dialysis. Transplant-related mortality was 6% after 100 days. Haematological complete response (CR) was obtained in nine (56%) and organ response in six (38%) patients. Nine out of 12 patients (75%) with kidney involvement exhibited a sustained clinical benefit at 12 months. Half of all the patients (n = 8) were alive after a median follow-up of 33 months, including two in continuous CR. This suggests that high-dose chemotherapy and ASCT are still valid treatment options in AL amyloidosis and that a significant number of patients with renal involvement might benefit from this approach.

Longitudinal analyses of renal lesions due to acute pyelonephritis in children and their impact on renal growth.

PURPOSE: Acute pyelonephritis is a common condition in children, and can lead to renal scarring. The aim of this study was to analyze the progression of renal scarring with time and its impact on renal growth. MATERIALS AND METHODS: A total of 50 children who had renal scarring on dimercapto-succinic acid scan 6 months after acute pyelonephritis underwent a repeat scan 3 years later. Lesion changes were evaluated by 3 blinded observers, and were classified as no change, partial resolution or complete disappearance. Renal size at time of acute pyelonephritis and after 3 years was obtained by ultrasound, and renal growth was assessed comparing z-score for age between the 2 measures. Robust linear regression was used to identify determinants of renal growth. RESULTS: At 6 months after acute pyelonephritis 88 scars were observed in 100 renal units. No change was observed in 27%, partial resolution in 63% and complete disappearance in 9% of lesions. Overall, 72% of lesions improved. Increased number of scars was associated with high grade vesicoureteral reflux (p = 0.02). Multivariate analysis showed that the number of scars was the most important parameter leading to decreased renal growth (CI -1.05 to -0.35, p <0.001), and with 3 or more scars this finding was highly significant on univariate analysis (-1.59, CI -2.10 to -1.09, p <0.0001). CONCLUSIONS: Even 6 months after acute pyelonephritis 72% of dimercapto-succinic acid defects improved, demonstrating that some of the lesions may be not definitive. The number of scars was significantly associated with loss of renal growth at 3 years.

Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.568.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 24 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 1230months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.57,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.