Adverse renal effects of check-point inhibitors (ICI) in cancer patients: Recommendations of the Onco-nephrology Working Group of the Spanish Society of Nephrology.

The most widely used approach in the immunotherapy treatment of cancer is the administration of monoclonal antibodies directed against regulatory molecules of immune control that inhibit the activation of T cells, the so-called check point inhibitors (ICI). ICI nephrotoxicity epidemiology and pathology; its diagnosis with or without kidney biopsy; the type and duration of treatment; the possibility of rechallenging after kidney damage; and its indication in patients with cancer and renal transplantation are certainly controversial. In the absence of definitive studies, this document is intended to specify some recommendations agreed by the group of Onconephrology experts of the Spanish Society of Nephrology in those areas related to ICI nephrotoxicity, in order to help decision-making in daily clinical practice in Onconephrology consultations.

Oral hydration as a safe prophylactic measure to prevent post-contrast acute kidney injury in oncologic patients with chronic kidney disease (IIIb) referred for contrast-enhanced computed tomography: subanalysis of the oncological group of the NICIR study.

BACKGROUND: T he objective of this study is to evaluate oral hydration compared to intravenous (i.v.) hydration in the prevention of post-contrast acute kidney injury (PC-AKI) in the oncologic subgroup of patients with stage IIIb chronic kidney disease (CKD) included in the NICIR study referred for elective contrast-enhanced computed tomography (CE-CT). MATERIAL AND METHODS: We performed a retrospective subanalysis of the oncological subgroup (174/228 patients, 74%) from a continuous prospective database of patients included in the recently published non-inferiority NICIR study. Patients received prophylaxis against PC-AKI with either oral hydration (500 mL of water 2 h before and 2000 mL during the 24 h after CE-CT) or i.v. hydration (sodium bicarbonate (166 mmol/L) 3 mL/kg/h starting 1 h before and 1 mL/kg/h during the first hour after CE-CT). The primary outcome was to compare the proportion of PC-AKI in the first 48 to 72 h after CE-CT in the two hydration groups. Secondary outcomes were to compare persistent PC-AKI, the need for haemodialysis, and the occurrence of adverse events related to prophylaxis in each group. RESULTS: Of 174 patients included in the subanalysis, 82 received oral hydration and 92 received i.v. hydration. There were no significant differences in clinical characteristics or risk factors between the two study arms. Overall the PC-AKI rate was 4.6% (8/174 patients), being 3.7% in the oral hydration arm (3/82 patients) and 5.4% (5/92 patients) in the i.v. hydration arm. The persistent PC-AKI rate was 1.2% (1/82 patients) in the oral hydration arm and 3.3% (3/92 patients) in the i.v. hydration arm. No patient required dialysis during the first month after CE-CT or had adverse effects related to the hydration regime. CONCLUSION: In oncological patients with stage IIIb CKD referred for elective CE-CT, the rate of PC-AKI in those receiving oral hydration did not significantly differ from that of patients receiving i.v. hydration.

Monographic consultation of onconephrology. Rationale and implementation.

The increase in demand for medical care for renal complications associated with neoplastic diseases is a reality in most nephrology departments. In response to this overall situation, the creation of healthcare models such as monographic consultations and develop training programs in Onconephrology could improve the care of these patients. Through an exploratory and descriptive study, we identified current situation of kidney involvement in cancer patients. The objective of the present study is to establish the criteria for specific assistance in the field of Onconephrology. For this, we have reviewed key aspects and analyzed the current situation in our country, through a survey addressed to all nephrologists through the Spanish Society of Nephrology., together with the experience of two Spanish centers. From this information, we have established some requirements and recommendations for the start-up of these consultations.

Monographic consultation of onconephrology. Rationale and implementation. / Consulta monográfica de onconefrología. Justificación y puesta en marcha.

The increase in demand for medical care for renal complications associated with neoplastic diseases is a reality in most nephrology departments. In response to this overall situation, the creation of healthcare models such as monographic consultations and develop training programs in onconephrology could improve the care of these patients. Through an exploratory and descriptive study, we identified current situation of kidney involvement in cancer patients. The objective of the present study is to establish the criteria for specific assistance in the field of onconephrology. For this, we have reviewed key aspects and analyzed the current situation in our country, through a survey addressed to all nephrologists through the Spanish Society of Nephrology, together with the experience of 2 Spanish centers. From this information, we have established some requirements and recommendations for the start-up of these consultations.

Onco-Nephrology: Cancer, chemotherapy and kidney. / Onco-Nefrología: cáncer, quimioterapia y riñón.

Chronic kidney disease (CKD), cancer and haematological diseases share areas of reciprocal influence. Cancer can affect the kidney either as glomerular lesions or as a result of the toxic effects of medication or radiation with acute (thrombotic microangiopathy, acute kidney injury, interstitial nephropathies among others) or chronic processes (worsening of CKD after nephrectomy due to renal cancer, interstitial fibrosis, hydroelectrolytic disorders). On the other hand, patients who require renal replacement therapy with dialysis and particularly with kidney transplantation are at high risk of onset of cancer due to the immunosuppression situation that they generate. In addition to conventional chemotherapy, innovative treatments have been developed: target agents against growth factors and their receptor; anti-angiogenic drugs; immunoregulatory proteins; cell cycle regulators; and enzyme inhibitors. Other immunotherapeutic approaches have also been developed, such as vaccines, adoptive cell therapy (CAR T cells) or development of antibodies. All these therapeutic advances will improve the outcomes against cancer and haematological diseases, but they are not free from secondary renal problems. Onco-Nephrology is already an important area for the Spanish Society of Nephrology with a large number of inter-consultations. Nephrologists need a better understanding of rapidly evolving areas of cancer biology and its treatment in order to become valued members of the cancer care team and to provide the best nephrology care possible.

Paricalcitol reduces oxidative stress and inflammation in hemodialysis patients.

BACKGROUND: Treatment with selective vitamin D receptor activators such as paricalcitol have been shown to exert an anti-inflammatory effect in patients on hemodialysis, in addition to their action on mineral metabolism and independently of parathyroid hormone (PTH) levels. The objective of this study was to evaluate the additional antioxidant capacity of paricalcitol in a clinical setting. METHODS: The study included 19 patients with renal disease on hemodialysis, of whom peripheral blood was obtained for analysis at baseline and three months after starting intravenous paricalcitol treatment. The following oxidizing and inflammatory markers were quantified: malondialdehyde (MDA), nitrites and carbonyl groups, indoleamine 2,3-dioxygenase (IDO), tumor necrosis factor alfa (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18) and C-reactive protein (CRP). Of the antioxidants and anti-inflammatory markers, superoxide dismutase (SOD), catalase, reduced glutathione (GSH), thioredoxin, and interleukin-10 (IL-10) levels were obtained. RESULTS: Baseline levels of oxidation markers MDA, nitric oxide and protein carbonyl groups significantly decreased after three months on paricalcitol treatment, while levels of GSH, thioredoxin, catalase and SOD activity significantly increased. After paricalcitol treatment, levels of the inflammatory markers CRP, TNF-α, IL-6 and IL-18 were significantly reduced in serum and the level of anti-inflammatory cytokine IL-10 was increased. CONCLUSIONS: In renal patients undergoing hemodialysis, paricalcitol treatment significantly reduces oxidative stress and inflammation, two well known factors leading to cardiovascular damage.

Beyond the cardiorenal anaemia syndrome: recognizing the role of iron deficiency.

Growing awareness that heart failure, renal impairment, and anaemia are frequent co-morbidities which can exacerbate one another in a vicious circle of clinical deterioration has led to the concept of the cardiorenal anaemia syndrome (CRAS). The role of iron deficiency within this complex interplay has been less well examined. Scrutiny of data from the recent FAIR-HF trial raises a new hypothesis: is it time for 'CRAS' to be supplemented with new acronyms such as CRIDS (cardiorenal-iron deficiency syndrome) or even CRAIDS (cardiorenal-anaemia-iron deficiency syndrome)? Iron deficiency occurs frequently in heart failure patients with or without anaemia. It not only impairs oxygen transport through reduced erythropoiesis, but adversely affects oxidative metabolism, cellular energetics, and immune mechanisms, and the synthesis and degradation of complex molecules such as DNA. One large observational study in patients with heart failure found iron deficiency to be an independent predictor of death or urgent heart transplantation (hazard ratio 1.58, 95% confidence interval 1.14-2.17, P = 0.005). In the FAIR-HF trial, i.v. iron therapy was associated with significant improvements in physical functioning in iron-deficient patients with heart failure, even in non-anaemic patients in whom haemoglobin levels did not change following i.v. iron administration. Key questions regarding the use of i.v. iron supplementation in the setting of heart failure merit exploration and could readily be answered by appropriately designed clinical trials. It is to be hoped that these important clinical trials are conducted, to permit a more subtle characterization of the patient's pathological condition and interventional requirements.

Anemia trials in CKD and clinical practice: refining the approach to erythropoiesis-stimulating agents.

As our knowledge of managing renal anemia with recombinant human erythropoietin has grown, new clinical challenges have emerged. Although initial observational studies produced important favorable results, troubling observations later came from 4 randomized controlled trials that assigned CKD patients to intervention with an erythropoiesis-stimulating agent (ESA) to achieve high hemoglobin levels (Hb). The difference between the observational studies and these randomized controlled trials comes from the observation of higher cardiovascular events when targeting higher Hb, but lower events once patients had achieved these Hb targets. In all of the 4 RCTs, the primary intervention was 'targeting' a higher Hb, and using higher dosages of ESA as the means. Therefore, the question to be solved is: what is harmful with recombinant human erythropoietin--targeting higher hemoglobin or achieving higher hemoglobin? Evidence supporting a relationship between ESA exposure and worse outcomes is not universal, and these comorbidities would require the administration of high doses. However, increasing ESA doses in hyporesponsive patients to achieve a specific target is not reasonable. Managing anemia in CKD patients is complex. It is affected by the underlying disease, comorbid conditions, the environment and several other factors that differ among patients. Thus, anemia management in these patients needs an individualized approach. Each patient should be treated according to a Hb target with the lowest effective ESA dose, while avoiding large fluctuations in Hb levels or prolonged periods outside the target. This strategy may necessitate changes to the ESA dose, dosing frequency and iron supplementation over the course of a patient's treatment, and proactive management of conditions that can affect ESA responsiveness. While all ESAs effectively increase Hb levels, differences with respect to route of administration, pharmacokinetics, and dosing frequency and efficiency should be considered to maximize the benefits of ESA treatment for the individual patient.

Maintenance of target hemoglobin level in stable hemodialysis patients constitutes a theoretical task: a historical prospective study.

Maintenance of target hemoglobin (Hb) values in hemodialysis patients treated with erythropoiesis-stimulating agents (ESAs) remains difficult. We examined Hb variability in the clinical setting in hemodialysis patients. Hemodialysis patients treated with ESAs who maintained the recommended Hb range of 11-13 g per 100 ml over 3 months and were not admitted to hospital, did not require transfusion, and did not experience any major clinical event during this period were followed prospectively for 1 year. Anemia events, Hb variation events (any value out of +/-1.5 g per 100 ml of the median Hb level in the total follow-up period for the individual patient), risk factors for anemia, and Hb variation events were assessed. We studied 420 patients (63% males, mean age 61 years), 222 received short-acting erythropoietin (EPO) and 198 long-acting darbepoetin. A total of 4654 blood samples (mean 11.1 per patient-year) were analyzed. Only 3.8% of patients were maintained within the target Hb levels (11-13 g per 100 ml) during 1 year. Hb variation events occurred in 20.8% of laboratory values and anemia events in 14.7%, with a median time to the first event of 3 months. Treatment with short-acting EPO (vs long-acting darbepoetin), change of ESA dose in the previous visit, resistance index, and hospitalization were significant risk factors for both anemia events and Hb variation events. Our results show that Hb values are rarely maintained within the recommended guidelines even in more stable hemodialysis patients. Hb variability is frequently associated with clinical events or ESA dose changes. Long-acting darbepoetin achieved better Hb stability than short-acting EPO.

Impact of treatment with calcimimetics on hyperparathyroidism and vascular mineralization.

Soft tissue calcification that involves primarily the medial portion of the arterial vasculature is a widely recognized and common complication of chronic kidney disease Vascular calcification (VC) causes increased arterial stiffness and contributes to the high cardiovascular mortality and morbidity in dialysis patients. The pathogenesis of VC is complex and includes factors that promote calcification and others that inhibit calcification. Studies in dialysis patients have shown a correlation between VC and a number of uremia-related factors. Overall, abnormalities in calcium and phosphate metabolism, such as hyperphosphatemia and a raised serum calcium-phosphorus product traditionally have been thought of as important determinants in patients with chronic renal failure. Common therapeutic interventions in secondary hyperparathyroidism have come under scrutiny for associations with the development of VC. Calcimimetics provide a means of controlling serum levels of parathyroid hormone in secondary hyperparathyroidism without increasing the calcium-phosphorus product and, more important, may lower the risk for VC in these patients.

The renal benefits of a healthy lifestyle.

Over the next decade, the number of patients with end-stage renal disease requiring treatment by dialysis may double, and even developed nations will have difficulty coping with this alarming increase. There is an urgent need to highlight the importance of modifiable risk factors as a basis for treatment strategies to prevent the development and progression of chronic kidney disease (CKD). This should include active extension of our current understanding of a healthy lifestyle.

Cinacalcet HCl: a novel therapeutic for hyperparathyroidism.

Hyperparathyroidism (HPT) is a significant clinical concern for patients with a variety of diseases, notably the secondary HPT associated with chronic kidney disease requiring dialysis. Secondary HPT is associated with elevated para-thyroid hormone (PTH) levels, decreased levels of 1,25 dihydroxyvitamin D, and disordered mineral levels (usually high calcium and phosphorus). If not controlled, secondary HPT can result in bone disease, vascular calcification, and ultimately, patient mortality. Established, conventional therapies, such as 1,25dihydroxyvitamin D analogues (vitamin D analogues) and phosphate binders, have proven to be inadequate in enabling patients to meet the National Kidney Foundation's-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) treatment goals for PTH, calcium and phosphorus levels. A novel therapeutic, cinacalcet HCl (formerly AMG 073; Sensipar in the US and Mimpara in Europe; Amgen, Inc.), binds directly to the calcium-sensing receptor (CaR) on the cells of the parathyroid gland, increasing the receptor's sensitivity to calcium and reducing PTH, serum calcium and phosphorus levels. Treatment with cinacalcet in clinical trials has safely and effectively improved achievement of the NKF-K/DOQI goals. Cinacalcet has also reduced serum calcium levels in patients with primary HPT, including parathyroid carcinoma, in the clinical trial setting. Evidence suggesting the utility of cinacalcet in these diseases and the potential for additional therapeutic applications will be discussed.

Bone disease in long-term adult kidney transplant patients with normal renal function.

BACKGROUND: In successful renal transplantation, the degree of renal function recovery is usually incomplete and information is scarce about the abnormalities of mineral metabolism in long-term adult renal recipients with normal renal function. This study was designed to investigate bone mineral metabolism in patients with a long-term normal functioning kidney. METHODS: Twenty-nine adult asymptomatic renal transplant (RT) recipients with stable graft function for more than 10 years and serum creatinine <2 mg/dL were studied. They were classified into two groups according to glomerular filtration rate: Group A (N = 12; nine men, three women)>70 mL/min (x: 126 +/- 55 mL/min) and Group B (N = 17; nine men, eight women) <70 mL/min (x: 56 +/- 11 mL/min). Circulating biochemical markers of bone remodelling, bone histomorphometry, and densitometry (lumbar spine and hip) were obtained to investigate bone disease in these patients. RESULTS: Serum PTH was slightly elevated in 10 patients (83%) in group A. Serum PTH levels were positively related to serum calcium, osteocalcin, BAP, telopeptide, OH-proline, and creatinine. There was no histologic data to support overactivity on bone in this group of patients, with only one showing high bone turnover. Mineralization was prolonged in 34% of patients. Twenty-two patients (75%) exhibited normal bone turnover. In the group with GFR>70 mL/min the prevalence of mineralization defect in the presence of normal serum levels of calcitriol suggested vitamin D resistance. Lumbar and femoral neck osteoporosis was present in 25% and 33% of patients in group A, and 23% and 53% in group B, respectively. T-score at lumbar spine was negatively correlated with months since transplantation. Patients under treatment with cyclosporine (CsA) showed increased concentrations of osteocalcin and D-pyr and higher lumbar bone mineral density (BMD), but bone histomorphometry was not influenced by CsA. CONCLUSION: Patients with long-term renal transplantation with normal renal function frequently present with slight increases in PTH, but without an effect on bone histology. CsA did not induce changes in bone histology and delayed mineralization was frequently observed.