Kidney Allograft Fibrosis: Diagnostic and Therapeutic Strategies.

Interstitial fibrosis with tubule atrophy (IF/TA) is the response to virtually any sustained kidney injury and correlates inversely with kidney function and allograft survival. IF/TA is driven by various pathways that include hypoxia, renin-angiotensin-aldosterone system, transforming growth factor-ß signaling, cellular rejection, inflammation, and others. In this review, we will focus on key pathways in the progress of renal fibrosis, diagnosis and therapy of allograft fibrosis. This review discusses the role and origin of myofibroblasts as matrix producing cells and therapeutic targets in renal fibrosis with a particular focus on renal allografts. We summarize current trends to use multiomic approaches to identify new biomarkers for IF/TA detection and to predict allograft survival. Furthermore, we review current imaging strategies that might help to identify and follow-up IF/TA complementary or as alternative to invasive biopsies. We further discuss current clinical trials and therapeutic strategies to treat kidney fibrosis.

[Bardoxolone: a new potential therapeutic agent in the treatment of autosomal dominant polycystic kidney disease?]

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic renal failure. The natural history of ADPKD is characterized by development of multiple bilateral renal cysts that progressively destroy the architecture of the parenchyma and lead to an enlargement in the total kidney volume (TKV) and to the decline of the renal function. Cyst growth activates the immune system response causing interstitial inflammation and fibrosis that contribute to disease progression. In recent years, the therapeutic toolkit available to the nephrologist in the treatment of ADPKD has been enriched with new tools, and in this context bardoxolone is classified as a potential therapeutic agent. It is a semisynthetic derivative of triterpenoids, a family of compounds widely used in traditional Asian medicine for their multiple effects. Bardoxolone exerts antioxidant activity by promoting the activation of Nrf2 (Nuclear factor erythroid2-derivative - 2) and the downregulation of the proinflammatory NF-kB (Nuclear factor kappa-light-chain-enhancer of activated B cells) signaling. Several pieces of evidence support the use of bardoxolone in the treatment of chronic kidney disease (CKD) documenting an effect on the increase of glomerular filtration rate (GFR). However, its use is limited to patients at risk of heart failure. The FALCON study will clarify the efficacy and safety of bardoxolone in the treatment of ADPKD.

Association of Drug Effects on Serum Parathyroid Hormone, Phosphorus, and Calcium Levels With Mortality in CKD: A Meta-analysis.

BACKGROUND: Serum parathyroid hormone (PTH), phosphorus, and calcium levels are surrogate outcomes that are central to the evaluation of drug treatments in chronic kidney disease (CKD). This systematic review evaluates the evidence for the correlation between drug effects on biochemical (PTH, phosphorus, and calcium) and all-cause and cardiovascular mortality end points in adults with CKD. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adults with CKD. SELECTION CRITERIA FOR STUDIES: Randomized trials reporting drug effects on biochemical and mortality end points. INTERVENTION: Drug interventions with effects on serum PTH, phosphorus, and calcium levels, including vitamin D compounds, phosphate binders, cinacalcet, bisphosphonates, and calcitonin. OUTCOMES: Correlation between drug effects on biochemical and all-cause and cardiovascular mortality. RESULTS: 28 studies (6,999 participants) reported both biochemical and mortality outcomes and were eligible for analysis. Associations between drug effects on surrogate biochemical end points and corresponding effects on mortality were weak and imprecise. All correlation coefficients were less than 0.70, and 95% credible intervals were generally wide and overlapped with zero, consistent with the possibility of no association. The exception was an inverse correlation between drug effects on serum PTH levels and all-cause mortality, which was nominally significant (-0.64; 95% credible interval, -0.85 to -0.15), but the strength of this association was very imprecise. Risk of bias within available trials was generally high, further reducing confidence in the summary correlations. Findings were robust to adjustment for age, baseline serum PTH level, allocation concealment, CKD stage, and drug class. LIMITATIONS: Low power in analyses and combining evidence from many different drug comparisons with incomplete data across studies. CONCLUSIONS: Drug effects on serum PTH, phosphorus, and calcium levels are weakly and imprecisely correlated with all-cause and cardiovascular death in the setting of CKD. Risks of mortality (patient-level outcome) cannot be inferred from treatment-induced changes in biochemical outcomes in people with CKD. Similarly, existing data do not exclude a mortality benefit with treatment. Trials need to address patient-centered outcomes to evaluate drug effectiveness in this setting.

Copper deficiency in patients with cystinosis with cysteamine toxicity.

OBJECTIVES: To assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in a small subset of patients with cystinosis. STUDY DESIGN: Thirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encoding copper transporters), LOX (encoding lysyl oxidase), and COL1A1 and COL1A2 (encoding type I procollagen) were analyzed in patients with (n = 6) and without (n = 5) toxicity. Fibroblast (pro)collagen synthesis was compared in patients with (n = 3) and those without (n = 2) cysteamine toxicity. RESULTS: All 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis. CONCLUSION: Patients with cystinosis with cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent cysteamine toxicity.

Hypercalciuria induced by a high dose of cinacalcet in a renal-transplant recipient.

The successful use of cinacalcet in dialysis patients and in patients with primary hyperparathyroidism has prompted transplant physicians to use it to treat renal-transplant patients with persisting hyperparathyroidism. However, in the setting of kidney transplantation, many questions remain unanswered, i.e. the time of initiation of cinacalcet after transplantation, its dosage and the side effects on kidney function all remain unknown. Herein, we report on a kidney-transplant recipient with persisting hyperparathyroidism who developed hypercalciuria afterreceiving high doses of cinacalcet. Cinacalcet was started 3 months after transplantation at a once-daily dose of 60 mg. Thereafter, the dosage was increased progressively because of persistant hyperparathyroidism and hypercalcemia. At a dose of 90 mg b.i.d, hypercalciuria occurred. The latter disappeared after reduction of cinacalcet dosage. Cinacalcet might be responsible for urinary calcium excretion, either by reduction of tubular calcium reabsorption via the reduction of PTH level, or by its direct effect on the calcium sensor receptor located in the upper thick ascending limb of the loop of Henle. We conclude that cinacalcet should be used with caution in renal-transplant patients. Further investigations are required to determine the best way to use this drug in this setting.

Endocrine and neuroanatomic features associated with weight gain and obesity in adult patients with hypothalamic damage.

PURPOSE: Obesity is a common consequence in patients with tumors of the hypothalamic region and of related treatment in children. Much less information is available on adult patients and long-term survivors. The aims of this study were to estimate the prevalence of obesity in adult patients with acquired structural hypothalamic damage and to define the characteristics of patients at greatest risk of obesity. METHODS: A retrospective study was conducted of 52 patients (25 women; median age at diagnosis, 44 years; range, 17 to 78 years) with tumors involving the hypothalamic region. These included 22 craniopharyngiomas, 24 pituitary adenomas, and six other hypothalamic tumors. Changes in body mass index were determined, magnetic resonance imaging scans were scored by a radiologist for tumor size and the extent of involvement of the hypothalamus, and current hormone replacement therapy was recorded, to identify possible features associated with new or worsened obesity (defined as a body mass index > or =30 kg/m(2) at the latest follow-up, which had increased by at least 2 kg/m(2) since diagnosis of the tumor). RESULTS: Serial body mass index data from diagnosis to the latest follow-up were available for 42 patients. After a median of 5 years (range, 1 to 19 years) of follow-up, most patients with hypothalamic damage were obese (52% [n = 22] vs. 24% [n = 10] at the time of diagnosis, P < 0.0001). In a multivariate model, use of desmopressin (odds ratio [OR] = 13; 95% confidence interval [CI]: 2.0 to 86; P = 0.007) and growth hormone replacement (OR = 7.6; 95% CI: 1.1 to 51; P = 0.04) were associated with new or worsened obesity during follow-up. No correlation was found between the initial size or location of the tumor and subsequent weight gain. CONCLUSION: Obesity is highly prevalent in adult survivors of hypothalamic tumors. Use of desmopressin and growth hormone therapy, but not size or location of the tumor, were associated with weight gain and obesity following diagnosis. These findings may be helpful in identifying patients at increased risk of obesity, to whom earlier intervention could be offered.

Reducing adverse drug events and medication errors using rapid cycle improvement.

The article describes Fairview Health System's participation in the Institute for Healthcare Improvement Breakthrough Series on adverse drug events and medication errors. Fairview commissioned an interdisciplinary team to design, plan, and lead activities focused on reducing adverse drug events and medication errors. This team managed, facilitated, or led 15 separate projects, each focusing on a specific aspect of the medications process. Specific systems improvements were identified, leading to reductions in errors or adverse events. As a result of this effort, Fairview has committed to a long-term plan to reduce the risk of adverse drug events and medication errors to the lowest possible rate.