The development of maintenance hemodialysis (HD) for end stage kidney disease patients is a success story that continues to save many lives. Nevertheless, intermittent renal replacement therapy is also a source of recurrent stress for patients. Conventional thrice weekly short HD is an imperfect treatment that only partially corrects uremic abnormalities, increases cardiovascular risk, and exacerbates disease burden. Altering cycles of fluid loading associated with cardiac stretching (interdialytic phase) and then fluid unloading (intradialytic phase) likely contribute to cardiac and vascular damage. This unphysiologic treatment profile combined with cyclic disturbances including osmotic and electrolytic shifts may contribute to morbidity in dialysis patients and augment the health burden of treatment. As such, HD patients are exposed to multiple stressors including cardiocirculatory, inflammatory, biologic, hypoxemic, and nutritional. This cascade of events can be termed the dialysis stress storm and sickness syndrome. Mitigating cardiovascular risk and morbidity associated with conventional intermittent HD appears to be a priority for improving patient experience and reducing disease burden. In this in-depth review, we summarize the hidden effects of intermittent HD therapy, and call for action to improve delivered HD and develop treatment schedules that are better tolerated and associated with fewer adverse effects.

Hemodialysis has saved many lives, albeit with significant residual mortality. Although poor outcomes may reflect advanced age and comorbid conditions, hemodialysis per se may harm patients, contributing to morbidity and perhaps mortality. Systemic circulatory "stress" resulting from hemodialysis treatment schedule may act as a disease modifier, resulting in a multiorgan injury superimposed on preexistent comorbidities. New functional intradialytic imaging (i.e., echocardiography, cardiac magnetic resonance imaging [MRI]) and kinetic of specific cardiac biomarkers (i.e., Troponin I) have clearly documented this additional source of end-organ damage. In this context, several factors resulting from patient-hemodialysis interaction and/or patient management have been identified. Intradialytic hypovolemia, hypotensive episodes, hypoxemia, solutes, and electrolyte fluxes as well as cardiac arrhythmias are among the contributing factors to systemic circulatory stress that are induced by hemodialysis. Additionally, these factors contribute to patients' symptom burden, impair cognitive function, and finally have a negative impact on patients' perception and quality of life. In this review, we summarize the adverse systemic effects of current intermittent hemodialysis therapy, their pathophysiologic consequences, review the evidence for interventions that are cardioprotective, and explore new approaches that may further reduce the systemic burden of hemodialysis. These include improved biocompatible materials, smart dialysis machines that automatically may control the fluxes of solutes and electrolytes, volume and hemodynamic control, health trackers, and potentially disruptive technologies facilitating a more personalized medicine approach.

Hemodiafiltration (HDF) combines both hemofiltration (HF) and hemodialysis in the same procedure. It was initially performed in adults in 1977, and later used in children in the early 1980s. The use of HDF allows a determined convective dialysis dose to be combined with the conventional urea dialysis dose. The dialysis session is better tolerated as a result of the effects of hemofiltration. On-line HDF, i.e., substitution fluid prepared from ultrafiltration of the ultrapure dialysate, can be performed safely due to recent advances in modern technology. However, despite interest and feasibility in children, the majority of pediatric dialysis units across the world still perform hemodialysis using highly permeable membranes, allowing back filtration in the filter and therefore a degree of convective flow, i.e., internal hemodiafiltration. In some countries, government restrictions prohibit the use of on-line hemodiafiltration, (such as the FDA recommendations in North America), and therefore it should not be used in these circumstances.

There is a rising incidence and prevalence of ESRD as a result of diabetes, with poor outcome and growing costs. Recently, two large trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL), showed that angiotensin receptor blockers (ARB) are more effective than traditional antihypertensive therapies at reducing progression toward ESRD in hypertensive patients with type 2 diabetes and overt nephropathy, regardless of changes in BP. The results of these two trials were used to compare the costs of ARB with those of renal replacement therapy (dialysis and renal transplantation) in an effort to establish whether ARB are cost-saving because they delay ESRD. Two different pharmacoeconomic approaches were used. With regard to the RENAAL trial, the number of ESRD days on losartan therapy as compared with the number of ESRD days on standard antihypertensive therapy was calculated, and the difference between the two was combined with the costs of ESRD. In the IDNT trial, Markov models were applied to assess the economic impact of irbesartan and to extrapolate future clinical and cost outcomes. Several economic analyses were performed in the United States and in European countries. Applying pharmacoeconomic models showed that treatment with ARB was associated with a greater improvement in life expectancy and lower total costs compared with amlodipine and standard antihypertensive therapy. Therefore, treating patients with type 2 diabetes, nephropathy, and hypertension with ARB is life- and cost-saving compared with traditional antihypertensive therapy.

Current methods of renal replacement therapy, combining convection and diffusion, are largely unsatisfactory in removing uremic toxins. Adsorption is a third mechanism that has been applied in extracorporeal therapy. This study evaluates the impact of hemodiafiltration with on-line regeneration of ultrafiltrate, a new two-step integrated sorbent system, on in vivo removal of a wide spectrum of solutes with different molecular weights.

Pre- and post-dialysis concentrations of small, medium-size, and large molecules were determined in ten patients undergoing regular hemodiafiltration treatments with on-line regeneration of the ultrafiltrate. We also analyzed, at different times of the same dialysis session, the inlet and outlet ultrafiltrate; the latter had been regenerated by the sorbent cartridge and was used as reinfusion liquid. The mean dialysis time was 260 +/- 21.2 min with a blood flow of 361 +/- 33.3 ml/min and a reinjection volume of 3.6 +/- 0.2 l/h.

Urea, creatinine and phosphate reduction ratio were respectively 69.8 +/- 8.2, 61.9 +/- 5.5, and 40.2 +/- 17.3%. Removal of medium-size markers such as calcitonin, osteocalcin, beta2-microglobulin, cystatin C, myoglobin and prolactin varied between 24 and 60%. The percentage of reduction for retinol binding protein and alpha1-microglobulin was negligible and we were unable to demonstrate any removal of alpha1-acid glycoprotein, pre-albumin, and albumin in the regenerated ultrafiltrate.

The hemodiafiltration with on-line regeneration of ultrafiltrate is a new hemodialysis system, which allows uremic toxin removal over a wide molecular-weight spectrum.

When introduced in the 1970s, convective dialysis therapies were considered an attractive alternative to hemodialysis (HD), but technical and economical limitations prevented wide clinical application. Today, these therapies (i.e. hemofiltration and hemodiafiltration) are receiving renewed interest from the renal community. The main reason is the disappointment with current chronic dialysis therapy, which despite continuous integration of technical and pharmaceutical progress, has not provided significantly improved survival. The recent HEMO study showed that HD, even when administered at high dose and with high-flux membranes, has reached the limit of benefit for a representative dialysis population. At the same time there is new evidence supporting convective therapies. The extended range of solutes that is removed by convection as opposed to diffusion includes many molecules associated with uremic symptoms and complications. The hemodynamic stability characteristic of convective therapies is confirmed also in comparison with modern HD. Observational data indicates a survival benefit for patients treated with large volumes of convection. Continuously applied convective therapies are the preferred choice in severe cases of acute renal failure, and new membrane development may take these therapies to new applications of blood purification in the intensive care unit.

Proteinuria is a risk factor for progression of chronic renal failure. A model of proteinuria-associated tubulointerstitial injury was developed and was used to examine the therapeutic effect of rapamycin. Two studies were performed. In study A, proteinuric rats were given sheep anti-Fx1A to induce experimental membranous nephropathy; control rats received normal sheep serum. Four weeks later, groups were subdivided and underwent laparotomy alone (two kidneys), nephrectomy alone (one kidney), or nephrectomy with polectomy (0.6 kidney). Renal function and morphology were evaluated 4 wk later. Whereas control rats never developed proteinuria, anti-Fx1A induced severe proteinuria. Proteinuria was unaffected by renal mass reduction. Proteinuric rats developed tubulointerstitial disease that was most severe in rats with 0.6 kidneys. Renal function (GFR) was reduced by loss of renal mass and was reduced further in proteinuric rats with 0.6 kidneys. In study B, the effect of rapamycin on the expression of candidate proinflammatory and profibrotic genes and the progression of proteinuria-associated renal disease were examined. All rats received an injection of anti-Fx1A and were nephrectomized and then divided into groups to receive rapamycin or vehicle. Gene expression, renal morphology, and GFR were evaluated after 4, 8, and 12 wk. Rapamycin reduced expression of the proinflammatory and profibrotic genes (monocyte chemotactic protein-1, vascular endothelial growth factor, PDGF, TGF-beta(1), and type 1 collagen). Tubulointerstitial inflammation and progression of interstitial fibrosis that were present in vehicle-treated rats were ameliorated by rapamycin. Rapamycin also completely inhibited compensatory renal hypertrophy. In summary, rapamycin ameliorates the tubulointerstitial disease associated with chronic proteinuria and loss of renal mass.