An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD.

Normal and Pathologic Concentrations of Uremic Toxins

https://www.kidney-international.org/article/S0085-2538(15)52297-7/pdf

The spectrum of podocytopathies : A unifying view of glomerular diseases

BACKGROUND: Reduction of proteinuria is associated with delayed progression of chronic kidney disease. Reports suggest that angiotensin-receptor blockers (ARBs) reduce proteinuria, but results are variable. The relative effect of ARBs and angiotensin-converting enzyme (ACE) inhibitors, and their combined administration, remains uncertain. PURPOSE: To establish the effect of ARBs versus placebo and alternative treatments, and the effect of combined treatment with ARBs and ACE inhibitors, on proteinuria. DATA SOURCES: English-language studies in MEDLINE and the Cochrane Library Central Register of Controlled Trials (January 1990 to September 2006), reference lists, and expert contacts. STUDY SELECTION: Randomized trials of ARBs versus placebo, ACE inhibitors, calcium-channel blockers, or the combination of ARBs and ACE inhibitors in patients with or without diabetes and with microalbuminuria or proteinuria for whom data were available on urinary protein excretion at baseline and at 1 to 12 months. DATA EXTRACTION: Two investigators independently searched and abstracted studies. DATA SYNTHESIS: Forty-nine studies involving 6181 participants reported results of 72 comparisons with 1 to 4 months of follow-up and 38 comparisons with 5 to 12 months of follow-up. The ARBs reduced proteinuria compared with placebo or calcium-channel blockers over 1 to 4 months (ratio of means, 0.57 [95% CI, 0.47 to 0.68] and 0.69 [CI, 0.62 to 0.77], respectively) and 5 to 12 months (ratio of means, 0.66 [CI, 0.63 to 0.69] and 0.62 [CI, 0.55 to 0.70], respectively). The ARBs and ACE inhibitors reduced proteinuria to a similar degree. The combination of ARBs and ACE inhibitors further reduced proteinuria more than either agent alone: The ratio of means for combination therapy versus ARBs was 0.76 (CI, 0.68 to 0.85) over 1 to 4 months and 0.75 (CI, 0.61 to 0.92) over 5 to 12 months; for combination therapy versus ACE inhibitors, the ratio of means was 0.78 (CI, 0.72 to 0.84) over 1 to 4 months and 0.82 (CI, 0.67 to 1.01) over 5 to 12 months. The antiproteinuric effect was consistent across subgroups. LIMITATIONS: Most studies were small, varied in quality, and did not provide reliable data on adverse drug reactions. Proteinuria reduction is only a surrogate for important progression of renal failure. CONCLUSION: The ARBs reduce proteinuria, independent of the degree of proteinuria and of underlying disease. The magnitude of effect is similar regardless of whether the comparator is placebo or calcium-channel blocker. Reduction in proteinuria from ARBs and ACE inhibitors is similar, but their combination is more effective than either drug alone. Uncertainty concerning adverse effects and outcomes that are important to patients limits applicability of findings to clinical practice.

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Meta-analysis: Effect of Monotherapy and Combination Therapy with Inhibitors of the Renin–Angiotensin System on Proteinuria in Renal Disease

Bone continuously undergoes building and degradation — a process known as bone remodelling This tightly controlled process can be dysregulated by chronic inflammation, and bone loss is commonly associated with inflammatory diseases Here, Redlich and Smolen discuss the molecular mechanisms mediating the inflammatory loss of bone and present strategies and agents for therapeutic intervention Bone is a tissue undergoing continuous building and degradation This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes Chronic inflammation can also perturb bone metabolism and promote increased bone loss Inflammatory diseases can arise all over the body, including in the musculoskeletal system (for example, rheumatoid arthritis), the intestine (for example, inflammatory bowel disease), the oral cavity (for example, periodontitis) and the lung (for example, cystic fibrosis) Wherever inflammatory diseases occur, systemic effects on bone will ensue, as well as increased fracture risk Here, we discuss the cellular and signalling pathways underlying, and strategies for therapeutically interfering with, the inflammatory loss of bone

Inflammatory bone loss: pathogenesis and therapeutic intervention.

Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/disease, including generation of ROS and...

Oxidant Mechanisms in Renal Injury and Disease

https://www.jrnjournal.org/article/S1051-2276(06)00098-7/pdf

Renal Disease in Obesity: The Need for Greater Attention

https://www.ajkd.org/article/S0272-6386(08)00467-8/pdf

Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial.

Background Post-transplantation bone disease is associated with a high degree of morbidity including pain and fractures. Glucocorticoid-induced osteoporosis on top of pre-existing renal osteodystrophy is considered the major pathogenic factor, while the role of non-glucocorticoid immunosuppressants is less well defined. Methods In this study, we investigated the influence of sirolimus (SRL) versus calcineurin inhibitor (CI)-based immunosuppressive regimens on biomarkers of bone resorption in renal transplant patients. In addition, the impact of SRL, tacrolimus and mycophenolate mofetil (MMF) on osteoclast activation and function was assessed in cell culture systems. Results Using this approach, we demonstrated reduced serum levels of bone resorption markers in patients treated with SRL after kidney transplantation compared to a CI-based regimen. In line with this observation, we detected profoundly reduced osteoclast differentiation and subsequently diminished hydroxyapatite resorption in the presence of SRL compared to MMF and tacrolimus in vitro. Moreover, SRL significantly reduced osteoclast precursor proliferation in vitro compared to tacrolimus and led to augmented apoptosis in osteoclast precursors. Conclusions Taken together, SRL was shown to inhibit osteoclast formation in vivo and in vitro. SRL thus may have the potential to balance osteoclast promoting effects of glucocorticoids and CI, thereby counteracting the development of accelerated osteoporosis in renal transplant recipients.

Impact of sirolimus, tacrolimus and mycophenolate mofetil on osteoclastogenesis—implications for post-transplantation bone disease

N-methyl-2-pyridone-5-carboxamide: A novel uremic toxin?

https://www.ajkd.org/article/S0272-6386(03)01456-2/pdf

Przemysław Rutkowski

Papers

Renal Disease in Obesity: The Need for Greater Attention

Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial.

Impact of sirolimus, tacrolimus and mycophenolate mofetil on osteoclastogenesis—implications for post-transplantation bone disease

N-methyl-2-pyridone-5-carboxamide: A novel uremic toxin?

Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis