Fighting the unbearable lightness of neglecting kidney health: the decade of the kidney.

A brief comprehensive overview is provided of the elements constituting the burden of kidney disease [chronic kidney disease (CKD) and acute kidney injury]. This publication can be used for advocacy, emphasizing the importance and urgency of reducing this heavy and rapidly growing burden. Kidney diseases contribute to significant physical limitations, loss of quality of life, emotional and cognitive disorders, social isolation and premature death. CKD affects close to 100 million Europeans, with 300 million being at risk, and is projected to become the fifth cause of worldwide death by 2040. Kidney disease also imposes financial burdens, given the costs of accessing healthcare and inability to work. The extrapolated annual cost of all CKD is at least as high as that for cancer or diabetes. In addition, dialysis treatment of kidney diseases imposes environmental burdens by necessitating high energy and water consumption and producing plastic waste. Acute kidney injury is associated with further increases in global morbidity, mortality and economic burden. Yet investment in research for treatment of kidney disease lags behind that of other diseases. This publication is a call for European investment in research for kidney health. The innovations generated should mirror the successful European Union actions against cancer over the last 30 years. It is also a plea to nephrology professionals, patients and their families, caregivers and kidney health advocacy organizations to draw, during the Decade of the Kidney (2020-30), the attention of authorities to realize changes in understanding, research and treatment of kidney disease.

Reducing the costs of chronic kidney disease while delivering quality health care: a call to action.

The treatment of chronic kidney disease (CKD) and of end-stage renal disease (ESRD) imposes substantial societal costs. Expenditure is highest for renal replacement therapy (RRT), especially in-hospital haemodialysis. Redirection towards less expensive forms of RRT (peritoneal dialysis, home haemodialysis) or kidney transplantation should decrease financial pressure. However, costs for CKD are not limited to RRT, but also include nonrenal health-care costs, costs not related to health care, and costs for patients with CKD who are not yet receiving RRT. Even if patients with CKD or ESRD could be given the least expensive therapies, costs would decrease only marginally. We therefore propose a consistent and sustainable approach focusing on prevention. Before a preventive strategy is favoured, however, authorities should carefully analyse the cost to benefit ratio of each strategy. Primary prevention of CKD is more important than secondary prevention, as many other related chronic diseases, such as diabetes mellitus, hypertension, cardiovascular disease, liver disease, cancer, and pulmonary disorders could also be prevented. Primary prevention largely consists of lifestyle changes that will reduce global societal costs and, more importantly, result in a healthy, active, and long-lived population. Nephrologists need to collaborate closely with other sectors and governments, to reach these aims.

Epidemiology of acute kidney injury in children worldwide, including developing countries.

In this review we summarize the world-wide epidemiology of acute kidney injury (AKI) in children with special emphasis on low-income countries, notably those of the sub-Saharan continent. We discuss definitions and classification systems used in pediatric AKI literature. At present, despite some shortcomings, traditional Pediatric Risk Injury Failure Loss and End Stage Kidney Disease (pRIFLE) and Kidney Disease Improving Global Outcomes (KDIGO) systems are the most clinically useful. Alternative definitions, such as monitoring serum cystatin or novel urinary biomarkers, including cell cycle inhibitors, require more long-term studies in heterogenous pediatric AKI populations before they can be recommended in routine clinical practice. A potentially interesting future application of some novel biomarkers could be incorporation into the "renal angina index", a concept recently introduced in pediatric nephrology. The most reliable epidemiological data on AKI in children come from high-outcome countries and are frequently focused on critically ill pediatric intensive care unit populations. In these patients AKI is often secondary to other systemic illnesses or their treatment. Based on a recent literature search performed within the framework of the "AKI 0by25" project of the International Society of Nephrology, we discuss the scarce and often inaccurate data on AKI epidemiology in low-income countries, notably those on the African continent. The last section reflects on some of the many barriers to improvement of overall health care in low-income populations. Although preventive strategies for AKI in low-income countries should essentially be the same as those in high-income countries, we believe any intervention for earlier detection and better treatment of AKI must address all health determinants, including educational, cultural, socio-economic and environmental factors, specific for these deprived areas.

Acute kidney injury in critically ill cancer patients: an update.

Patients with cancer represent a growing group among actual ICU admissions (up to 20 %). Due to their increased susceptibility to infectious and noninfectious complications related to the underlying cancer itself or its treatment, these patients frequently develop acute kidney injury (AKI). A wide variety of definitions for AKI are still used in the cancer literature, despite existing guidelines on definitions and staging of AKI. Alternative diagnostic investigations such as Cystatin C and urinary biomarkers are discussed briefly. This review summarizes the literature between 2010 and 2015 on epidemiology and prognosis of AKI in this population. Overall, the causes of AKI in the setting of malignancy are similar to those in other clinical settings, including preexisting chronic kidney disease. In addition, nephrotoxicity induced by the anticancer treatments including the more recently introduced targeted therapies is increasingly observed. However, data are sometimes difficult to interpret because they are often presented from the oncological rather than from the nephrological point of view. Because the development of the acute tumor lysis syndrome is one of the major causes of AKI in patients with a high tumor burden or a high cell turnover, the diagnosis, risk factors, and preventive measures of the syndrome will be discussed. Finally, we will briefly discuss renal replacement therapy modalities and the emergence of chronic kidney disease in the growing subgroup of critically ill post-AKI survivors.

Influence of severity of illness on neutrophil gelatinase-associated lipocalin performance as a marker of acute kidney injury: a prospective cohort study of patients with sepsis.

BACKGROUND: The role of neutrophil gelatinase-associated lipocalin (NGAL) as a diagnostic marker for acute kidney injury (AKI) in sepsis is still debated. We hypothesized that in sepsis, the performance of serum(s) and urinary(u) NGAL can be negatively impacted by severity of illness and inflammation, and that both uNGAL and sNGAL levels can be increased regardless of presence of AKI. METHODS: One hundred and seven patients with sepsis were included. uNGAL and sNGAL were measured at admission (T0) and 4 hours (T4) and 24 hours later (T24). Transient and intrinsic AKI were respectively defined as AKI according to RIFLE during the first 72 hours that did or did not recover to "no AKI" in the following 72 hours. Patients were classified according to tertiles of CRP and APACHE II score increase. The relationship between sNGAL and uNGAL was assessed by linear regression. RESULTS: Fifty-seven patients developed transient and 22 intrinsic AKI. Prevalence of transient and intrinsic AKI were higher in patients with versus without septic shock (OR (95% CI): 3.3(1.4-8.2)). uNGAL was associated with sNGAL, and this with parallel slopes but different intercepts for AKI (Y = 0.87*X + 314.3, R2 = 0.31) and no AKI (Y = 0.87*X + 20.1, R2 = 0.38). At T4, median uNGAL and sNGAL levels were higher in septic patients with versus without shock but this is independent of AKI ((545 ng/mL vs 196 ng/ml for uNGAL and 474 ng/ml vs 287 ng/ml for sNGAL (both P = 0.003)). Both uNGAL and sNGAL levels increased with tertiles of CRP and APACHE II score increase. CONCLUSIONS: Serum and uNGAL levels are influenced by severity of illness and inflammation, and this was found to be independent of the presence of AKI. There is a strong correlation between sNGAL and uNGAL levels in patients with sepsis, indicating that increased levels of uNGAL can also be due to overspill from the systemic circulation, blurring the discriminative value of NGAL as a biomarker for AKI in patients with sepsis.

Nephrotoxicity of recent anti-cancer agents.

Cancer patients may develop a variety of kidney lesions that impair not only their immediate survival but also limit the adequate treatment of the underlying malignant process. This review summarizes the nephrotoxic potential of some of the most recently developed anti-cancer drugs, focusing on those interfering with the vascular endothelial growth factor and epidermal growth factor receptor pathways and mammalian target of rapamycin inhibitors. Thrombotic microangiopathy (haemolytic-uraemic syndrome), proteinuria, hypertension and magnesium depletion are the most common side effects. Also the risk for developing acute kidney injury in patients with advanced prostate cancer undergoing androgen deprivation therapy is discussed.

How to use biomarkers efficiently in acute kidney injury.

We discuss the performance of novel biomarkers in acute kidney injury (AKI). Comparison of the areas under the receiver operating characteristic curves of several biomarkers with some clinical and/or routine biochemical outcome parameters reveals that none of the biomarkers has demonstrated a clear additional value beyond the traditional approach in clinical decision making in patients with AKI. Unscrutinized use of these biomarkers may distract from adequate clinical evaluation and carries the risk of worse instead of better patient outcome.

Electrolyte disturbances and acute kidney injury in patients with cancer.

The interrelation between kidney disease and cancer is complex and reciprocal. Among the most frequent cancer-associated kidney diseases are the electrolyte and acid-base disturbances, which occur frequently and often are associated with an ominous prognosis, and acute kidney injury. Tumor lysis syndrome is a potentially life-threatening condition that frequently occurs in patients with a high tumor burden and high cellular turnover after cytotoxic therapy (including steroids in steroid-sensitive hematologic malignancies). Electrolyte and acid-base disturbances are the consequence of neoplastic spread, anticancer treatment, or, more rarely, paraneoplastic phenomena of all types of tumors. This article reviews hyponatremia and hypernatremia, hypokalemia and hyperkalemia, hypomagnesemia, hypercalcemia and hypocalcemia, hypophosphatemia, and the most important disturbances in acid-base balance in cancer patients. Acute kidney injury (AKI) is a frequent occurrence in cancer patients and has the potential to substantially alter the outcome of patients with cancer and jeopardize their chances of receiving optimal cancer treatment and a potential cure. As in many other circumstances, the etiology of AKI in cancer patients is multifactorial. Initiation and/or continuation of dialysis in the AKI cancer patient should be based on the general clinical condition and overall life expectancy and the personal patient expectations on quality of life after eventual recovery.

The prevention of acute kidney injury an in-depth narrative review: Part 2: Drugs in the prevention of acute kidney injury.

The second part of this in-depth clinical review focuses on drugs used in the prevention of AKI in the patient at risk and/or in the management of the patient with incipient AKI. Among the drugs used to maintain a normal renal perfusion pressure, norepinephrine and vasopressin are most commonly used in hypotensive critically ill patients. The most recent RCT did not find a difference between low-dose vasopressin plus norepinephrine and norepinephrine alone in patients with septic shock, suggesting that either approach is reasonable. However, vasopressin may be beneficial in the less severe septic shock subgroup. Loop diuretics may convert an oliguric into a non-oliguric form of AKI that may allow easier fluid and/or nutritional support of the patient. Volume overload in AKI patients is common and diuretics may provide symptomatic benefit in that situation. However, loop diuretics are neither associated with improved survival, nor with better recovery of renal function in AKI. Among the renal vasodilating drugs, the routine administration of dopamine to patients for the prevention of AKI or incipient AKI is no longer justified. On the other hand, although additional studies may be warranted, fenoldopam may appear to be a likely candidate for the prevention of AKI, particularly in critically ill patients, if the positive results obtained in some recent studies are confirmed. Trials with natriuretic peptides were in general inconclusive but despite the fact that nesiritide is currently approved by the FDA only for the treatment of heart failure, this vasodilator may in the future play a role in the prevention of AKI, particularly in association with heart failure and cardiac surgery. The most recent trials seem to confirm a potential positive preventive effect of N-acetylcysteine (NAC), particularly in contrast-induced nephropathy (CIN), NAC alone should never take the place of IV hydration in patients at risk for CIN; fluids likely have a more substantiated benefit. At present, initiation of statin therapy for the prevention of CIN cannot be recommended, but these drugs should not be stopped before a radiological intervention in patients on chronic statin therapy. Rasburicase is very effective in the prevention of acute tumour lysis syndrome. Erythropoietin (EPO) has tissue-protective effects and prevents tissue damage during ischaemia and inflammation, and currently trials are performed with EPO in the prevention of AKI post-cardiac surgery, CIN and post-kidney transplantation. From this review it becomes clear that single-drug therapy will probably never be effective in the prevention of AKI and that multiple agents may be needed to improve outcomes. In addition, drugs should be administered early during the course of the disease.

Acute renal problems in the critically ill cancer patient.

PURPOSE OF REVIEW: This review addresses three major topics relevant for the management of renal problems in the critically ill cancer patient; the assessment of kidney function in patients with cancer, serious water and electrolyte metabolism disturbances and acute kidney injury secondary to hematological and nonhematological malignancies. RECENT FINDINGS: In all cancer patients, renal function (urinalysis for proteinuria or albuminuria and serum creatinine to estimate glomerular filtration rate) should be tested when they first present, at initiation and change of cancer therapy as well as during follow-up. However, the different proposed formulae for estimation of the glomerular filtration rate should be used with caution. Electrolyte abnormalities associated with the refeeding syndrome are common, yet underappreciated, and occur typically in acutely ill, malnourished hospitalized patients who are administered intravenous or enteral nutrition. Currently available data on acute kidney injury and its consequences suggest that acute kidney injury has the potential to substantially alter the outcome of patients with cancer and jeopardize their chances of receiving optimal cancer treatment and a potential cure. SUMMARY: The complex management of the numerous renal complications of the critically ill cancer patient needs a multidisciplinary approach in which the nephrologist, intensivist and oncologist all play a pivotal role.

Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients.

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked condition originating from a deficiency in alpha-galactosidase, a lysosomal enzyme. Multi-organ involvement ensues in early adulthood and vital organs are affected: the kidneys, brain, heart. Several reports however suggest that AFD is underdiagnosed. METHODS: We screened a kidney transplant population using a two-tier approach. The first tier was the determination of alpha-galactosidase A (AGALA) activity using a dried blood spot on filter paper (DBFP); in the second tier, patients with the lowest alpha-galactosidase levels were further subjected to mutation analysis of the GLA gene. RESULTS: From the database of 2328 patients, 1233 subjects met the inclusion criteria. Finally, after informed consent, 673 patients were screened (54.5%-395 women and 278 men). DBFP analysis resulted in a mean AGALA of 2.63 +/- 2.48 micromol/L/h (2.5 and 97.5 percentile were 0.0001 and 5.07 micromol/L/h, respectively). Eleven patients were subjected to further genetic analysis. In a male patient a pathogenic missense mutation p.Ala143Thr (c.427A>G) was identified. CONCLUSIONS: Our results show that the proposed approach can detect AFD patients in a until now seldomly screened high-risk group: kidney transplant patients. We conclude that screening for AFD in high-risk populations is a cost-effective, technically feasible and clinically valuable objective.

Two-tier approach for the detection of alpha-galactosidase A deficiency in a predominantly female haemodialysis population.

INTRODUCTION: Fabry's disease (AFD) is an X-linked lysosomal storage disease, resulting from a deficiency in alpha-galactosidase A (AGALA). Untreated, this leads to precocious failure of vital organ function and death. As enzyme replacement therapy is available, it is of vital importance that affected individuals can be traced. MATERIALS AND METHODS: We set up a screening in the Flemish haemodialysis population using a two-tier approach. The first tier was a determination of alpha-galactosidase A activity using a dried blood spot on filter paper, in the second tier, patients with the lowest alpha-galactosidase levels were further subjected to mutation analysis of the GLA gene. RESULTS: 1284 patients (1047 women, 237 men) were evaluated for inclusion, eliminating patients with definite renal diagnoses. Total 922 patients (71.8 %) were screened (742 women, 180 men). Fifty seven patients were subjected to further genetic analysis. Three GLA mutation carriers were identified: two apparently nonrelated female patients carry the missense mutation p.Ala143Thr (c.427G > A), a missense mutation p.Trp236Arg (c.706T > C) was identified in a man. While the male patient had been clinically diagnosed with AFD, the female patients had remained unrecognized. Additional family based screening resulted in the identification of nine mutation carriers (four males and five females). DISCUSSION: We demonstrated that the prevalence of GLA mutation carriers in our haemodialysis population is 0.3%. Our results show that the proposed approach accurately detects AFD patients. We conclude that screening for AFD in high risk populations is a cost-effective, technically feasible and clinically valuable objective.

Belgium's mixed private/public health care system and its impact on the cost of end-stage renal disease.

Belgium has a mixed, public-private health care system, with state-organized reimbursements but private providers. The system is fee for service. For end-stage renal disease (ESRD), the fee-for-service system discourages preventive strategies, early referral to the nephrology unit, and the use of home-based therapies. The aging of the general population is reflected in the rapidly increasing number of very old dialysis patients, requiring more complicated and, therefore, more costly care. As dialysis costs increase, the ability to provide unrestricted access to dialysis treatment may be unsustainable. To aid in decision-making processes, nephrologists must be aware of financial and organizational issues.

Chronic kidney disease-mineral-bone disorder: a new paradigm.

Disturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified on the basis of bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) recently sponsored a Controversies Conference to evaluate this definition. The recommendations were that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD and (2) the term CKD-mineral and bone disorder (CKD-MBD) be used to describe the broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD. CKD-MBD is manifested by an abnormality of any one or a combination of the following: laboratory-abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; bone-changes in bone turnover, mineralization, volume, linear growth, or strength; and calcification-vascular or other soft-tissue calcification. The pathogenesis and clinical manifestations of these components of CKD-MBD are described in detail in this issue of Advances in Chronic Kidney Disease.

Peripheral arterial disease in patients with end-stage renal disease: observations from the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Patients with end-stage renal disease are at high risk for cardiovascular morbidity and mortality. The aims of the present study were to describe the prevalence of peripheral arterial disease (PAD) and its effects on prognosis and health-related quality of life (HRQOL) in an international cohort of patients on hemodialysis. METHODS AND RESULTS: Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, international, observational study of hemodialysis patients (n=29,873), were analyzed. Associations between baseline clinical variables and PAD were evaluated by logistic regression analysis. Cox regression models were used to test the association between PAD and risk for all-cause mortality, cardiac mortality, and hospitalization. PAD was diagnosed in 7411 patients (25.3%) with significant geographic variation. Traditional cardiovascular risk factors including age, male sex, diabetes, hypertension, and smoking were identified, together with the duration of hemodialysis, as significant correlates of PAD. Diagnosis of PAD was associated with increased all-cause mortality (hazard ratio [HR]=1.36; P<0.0001), cardiac mortality (HR=1.43; P<0.0001), all-cause hospitalization (HR=1.19; P<0.0001), and hospitalization for a major adverse cardiovascular event (HR=2.05; P<0.0001). HRQOL questionnaires revealed physical health scores that were significantly lower in PAD compared with non-PAD patients (P<0.0001). CONCLUSIONS: PAD is common in hemodialysis patients and is associated with increased risk of cardiovascular mortality, morbidity, and hospitalization and reduced HRQOL.

Epidemiology and prognostic implications of contrast-induced nephropathy.

Contrast-induced nephropathy (CIN), usually defined as an increase in serum creatinine of 0.5 mg/dL (44.2 mumol/L), or a 25% increase from the baseline value 48 hours after the procedure, is a common and potentially serious complication of the use of iodinated contrast media in patients at risk of acute renal injury. It is an important cause of hospital-acquired renal failure, responsible for approximately 11% of cases. CIN may be difficult to distinguish from cholesterol embolization, another cause of postprocedure renal impairment. The reported incidence of CIN varies depending on the patient population studied. The impact of postprocedural renal impairment on clinical outcomes has been evaluated most extensively in patients undergoing percutaneous coronary intervention. CIN is associated with increased mortality both in hospital and at 1 year. A higher incidence of in-hospital and late cardiovascular events, as well as longer hospital stays, has been reported in patients developing CIN. In a small proportion of patients, CIN is severe enough to require dialysis, and these patients have a particularly poor prognosis. Many of the risk markers for CIN are also predictive of a worse prognosis.

Pathophysiology of contrast-induced nephropathy.

Contrast-induced nephropathy (CIN) is the third leading cause of acute kidney injury in hospitalized patients and is associated with significant patient morbidity. The pathogenesis of CIN is complex and not fully understood, but iodinated contrast agents induce intense and prolonged vasoconstriction at the corticomedullary junction of the kidney. Moreover, high-osmolar dyes directly impair the autoregulatory capacity of the kidney through a loss of nitric oxide production. These effects, coupled with direct tubular toxicity of contrast media, lead to overt acute tubular necrosis and the syndrome of CIN.

Baseline renal function screening.

Renal impairment at baseline (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2)) is the most important risk marker to predict the risk of contrast-induced nephropathy (CIN) in patients receiving iodinated contrast media. Hence, it is important to assess renal function before administration of contrast medium to ensure that appropriate steps are taken to reduce the risk. Serum creatinine alone does not provide a reliable measure of renal function, hence the National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI) recommends that clinicians should use an eGFR calculated from the serum creatinine as an index of renal function. The CIN Consensus Working Panel agreed that eGFR should be determined before contrast administration, using the abbreviated Modification of Diet in Renal Disease (MDRD) formula, recommended by K/DOQI as the preferred equation for the calculation of eGFR in adults. Where a serum creatinine measurement or eGFR is not available, a simple survey or questionnaire can be used before contrast agent administration to identify patients at higher risk for CIN compared with the general population. In emergency situations, where the benefit of very early imaging outweighs the risk of waiting, the CIN Consensus Working Panel agreed that the procedure can be performed without assessment of renal function.

Risk prediction of contrast-induced nephropathy.

In order to make appropriate decisions about clinical management, it is important for physicians to be able to stratify patients according to their risk for contrast-induced nephropathy (CIN). The most important risk marker for nephropathy after exposure to iodinated contrast media is preexisting renal impairment. The risk of CIN is elevated and becomes clinically important in patients with chronic kidney disease characterized by an estimated glomerular filtration rate <60 mL/min per 1.73 m(2). In patients with renal impairment, diabetes mellitus amplifies the risk of CIN and complicates postprocedure management. Other markers associated with an increased risk of CIN include cardiovascular disease, periprocedural hemodynamic instability, use of nephrotoxic drugs, and anemia. The effect of risk factors is additive, and the presence of multiple risk factors in the same patient can create a very high risk for CIN and acute renal failure requiring dialysis. Risk models incorporating baseline and periprocedural characteristics have been developed using data from large databases of percutaneous coronary intervention patients. These schemes are potentially valuable, but at present the most practical approach to risk prediction is based on a simple model incorporating renal function and diabetes mellitus.