Chronic kidney disease (CKD) is a major public health problem worldwide, so its early detection is considered a top priority to establish strategies to prevent the progression to advanced stages of the disease and its complications.1–3

In Spain, the results of the Nutrition and Cardiovascular Risk Study (ENRICA)4 have shown a prevalence of any CKD in of its stages of 15.1% for the general population, similar to the 14.4% of the population attended in primary care in the IBERICAN study. (Identification of the Spanish population with cardiovascular and kidney risk).5 Both studies show that age and cardiovascular disease increase the prevalence of CKD. These current data differ from the 9.24% obtained in the old EPIRCE study (Epidemiology of Chronic Renal Insufficiency in Spain).6 This is partly due to substantial methodological differences between the studies, but could also indicate evolutionary changes over time. All these epidemiological data support the fact that CKD is an important health problem.

The epidemiological importance of CKD is related not only to its high prevalence but also to the significant decrease in quality of life, high morbidity and mortality, and the health and social cost that this entails. In this scenario, Primary Care (PC) is a fundamental mainstay not only in the early detection of CKD, but also in the management of progression factors and even in the management of the initial complications and, with this perception, this document is aimed at multidisciplinary collaboration for the detection and management of CKD.

Seven years have passed since the publication of the previous consensus document with the participation of ten scientific societies, and it has been a actual reference for the management of renal patients. From then until now, our KDIGO reference guide (Kidney Disease Improving Global Outcomes),7 published in 2012, has not been updated in this field. Thus, we have considered that it was appropriate to update its contents in specific areas based on the same structure of the document published in 2014. The methodology used is based on the critical review of the main published studies, clinical guidelines on CKD, the new KDIGO guides on specific topics and the few randomized clinical trials performed in CKD patients. This analysis allows to provide some recommendations or suggestions based on the best available evidence, as well as to report on new aspects that have gained importance in CKD.

The international organization KDIGO defines CKD as the presence of alterations in kidney structure or function for a period longer than three months, regardless of the cause7 and with health consequences exposed by different criteria (Table 1):

• a)

  The decrease in glomerular filtration rate (GFR) (< 60mL/min/1.73m 2), either measured with exogenous markers (GFRm) or estimated by equations from endogenous markers (GFR).

• b)

  The presence of renal injury or damage, referred to the existence of structural or functional alterations of the kidney detected directly with a renal biopsy or indirectly by the presence of albuminuria, proteinuria, alterations in the urinary sediment, in imaging tests, hydroelectrolytic abnormalities or another type of alterations of tubular origin or history of renal transplantation.

It should be noted that a single criterion of the two above mentiones is sufficient to make the diagnose of CKD, and it should be stressed that the presence of kidney injury markers is essential to diagnose a patient as CKD if their GFR is > 60mL/min /1.73m2.8

In recent years, an important debate has arisen about whether the criterion of a decreased GFR<60mL /min/1.73m 2 should vary depending on the age of the patients, with some authors advocating that in those over 65 years of age be modified to <45mL /min/1.73m2 and if less than 40 years of age change it to <75mL /min/1.73m 2 since the range of GFR associated with increased mortality changes with the age.9,10 The use of different GFR thresholds according to age as a diagnostic criterion for CKD produces an overall decrease in the prevalence of CKD, avoids its overdiagnosis in the elderly population without other CKD criteria and low probability of CKD progression, and allows earlier detection of CKD in the younger population.

Although the definition of CKD has remained unchanged since its initial description in 2002,29 there have been some universally accepted changes in its staging, but none since the publication of the Consensus Document in 2014.13

This classification considers a division of six risk categories according to the GFR (G1-G5) that are complemented by three risk categories according to the UACR (A1-A3) (Table 4). The decrease in GFR and the increase in the UACR are associated with an increase in adverse events (overall mortality, cardiovascular mortality, kidney failure requiring dialysis or transplantation, acute kidney failure and progression of kidney disease) (Table 5). The coexistence of a decreased GFR and an increased UACR multiplies the risk of adverses events. Patients that starts dialysis are included in the G5D category and, if they are transplanted they are stratified into stages G1T to G5T according to their GFR. It should be noted that in the KDIGO7 guidelines and in other studies performed in our country,4 more than 80% of the subjects with CKD (80.6%; 12.2% of the total sample) corresponded to moderate risk of cardiorenal complications, which establishes an important margin for both cardiovascular and renal prevention.

Table 5.

Staging and prognosis of CKD by glomerular filtration rate and albuminuria.

GFR: glomerular filtration rate; CKD: chronic kidney disease.

Note: Colors show the adjusted relative risk for five events (overall mortality, cardiovascular mortality, kidney failure treated with dialysis or transplantation, acute kidney injury, and kidney disease progression) from a meta-analysis of general population cohorts. The lowest risk corresponds to the color green ("low risk" category and, if there is no data on kidney damage, it cannot be classified as CKD), followed by the color yellow ("moderately increased" risk), orange ("high risk") and red (“very high risk”), which express increasing risks for the events mentioned (adapted from reference7).

Finally, it is important to take into account that the diagnosis and staging of CKD is independent of the cause of renal disease, however it is essential to bear in mind the cause of CKD in relation to the diagnosis and prognosis. For this reason, the international guidelines particularly recommend taking into account the concept of cause, grade, albuminuria (CGA).7,8 In this regard, it is emphasized that pathologies such as urinary obstruction, nephritic syndromes and/or glomerulonephritis/vasculitis, renal vascular disease, myeloma or other systemic diseases with renal involvement should have specific treatments.

In a recently published KDIGO document on the unification of nomenclature for kidney function and CKD, it is preferred to avoid the term end-stage kidney disease as it is not a patient-sensitive term and has stigmatizing connotations.24 This same document insists that albuminuria or proteinuria should not be used as equivalents of decreased kidney function, since they are not markers of kidney function but only markers of structural kidney injury.

These changes, among others, are discussed in an editorial article in the journal of the Spanish Society of Nephrology that brings together a new international initiative on the unification of nephrology nomenclature in Spanish developed by different societies.30

The average rate of annual decrease in GFR is highly variable, being higher in patients with significant proteinuria, DM or hypertension that is not optimally controlled.

Predictors of renal progression are shown in Table 7.40–53

In a recent analysis of 264,296 patients with GFR<30mL/min/1.73m 2 the most relevant factors in the progression of kidney disease requiring RRT were low GFR, DM, black race, male sex, systolic BP≥140mmHg and albuminuria.54 From this analysis, a calculator based on a mathematical formulation has been built to estimate the risk of starting RRT, cardiovascular events and death: http://ckdpcrisk.org/lowgfrevents/.

Frailty is defined as syndrome that entails a decreased of reserve and reduced resistance to stressors, resulting from the accumulation of deficits in multiple physiological systems, which ends up causing vulnerability.55

The prevalence of frailty in CKD is higher than in other cardiovascular disrases; frailty increases progressively as GFR decreases, particularly from GFR<45mL/min/1.73m 2 ; it is an independent risk factor for hospitalization and mortality from any cause, especially in dialysis patients, in whom it reaches prevalences of up to 73% (preferably using Fried phenotypes) compared to 7% in stage G1-G4.56,57

There are different scales to assess frailty providing different results. One of the most used and recommended is the five-item FRAIL questionnaire (Table 8). This scale evaluates frailty according to phenotypic expression through the combination of five conditions, each one valued as one point. Patients are classified according to their health status as: frail (3-5 points), pre-frail (1-2 points), and robust (0 points).58 This quick and easy to apply questionnaire has been validated in multiple geriatric settings, although it loses discriminative capacity in populations with a high prevalence of frailty, as is the case of hemodialysis patients.

In patients with CKD, the most used scale is the Fried Phenotypes55 (Table 9).

In summary, frailty assessment is recommended in CKD patients, as a measure of physiological reserves, to assess prognosis and help make therapeutic decisions, including replacement therapies. The optimal tool for its evaluation in patients with CKD has not been established, although the Fried phenotypes are the most used and the FRAIL questionnaire can help detect frailty in dialysis patients.

Referral to Nephrology (Fig. 1) will be made taking into account the stage of CKD, the rate of progression of CKD, the degree of albuminuria, the presence of alarm signs, associated comorbidity and the functional status of the patient.34,60,61 In general CKD presents few sympytoms and it is often asymptomatic until very advanced stages; therefore its follow upo is highly dependent on monitoring laboratory results. The risk of cardiovascular events is higher than that of progression to dialysis.54 In many cases, renal progression is slow without requiring special measures, except for control of cardiovascular risk factors and avoidance of nephrotoxicity. For this reason, suitable circuits must be created that begin with a virtual (telematic) consultation between the doctor who is going to refer the patient and the Nephrology Department for an initial assessment, since in many cases this channel may fulfill the consultation, or clarify doubts about the follow-up of patients with advanced age, decreased GFR and little progression. In this way, the shifts of the patient and family, as well as unnecessary or repeated tests, can be avoided.

Fig. 1.

Algorithm for diagnosis and shared care between Primary Care and Nephrology.

CKD: chronic kidney disease; AHT: arterial hypertension; GFR: estimated glomerular filtration rate; UACR: urine albumin to creatinine ratio; RRT: renal replacement therapy; CVRF: cardiovascular risk factors; DM: diabetes mellitus.

(0.84MB).

In general, patients should be referred to a specialist in Nephrology if they present albuminuria > 300mg/g, albuminuria of any grade accompanied by glomerular microhematuria (hematuria of a non-urological cause) or those with CKD G4 or G5 (GFR<30mL/min/1.73m 2) (except > 80 years without renal progression, albuminuria < 300mg/g, no alarming signs and without a plan or decision to undergo RRT (see below).

The frequency of monitoring and visits for patients with CKD is shown in Table 10; it will depend on the cause of the CKD, the the rate of change of GFR/creatinine and albuminuria (easily visible in computer applications of health systems), the presence of comorbidities, acute intercurrent illnesses or hospitalizations, especially heart failure, and changes made in treatment. In this regard, it should be remembered that in some situations monitoring should be performed after the introduction of some drugs such as RAAS inhibitors, SGLT2 inhibitors, increased doses of diuretics, suspicion of renal impairment due to NSAIDs, adjustment of direct-acting oral anticoagulants (DOACs) or after occurrence of unexpected hypoglycemia in diabetics.

Table 10.

Visit monitoring frequency (number of annual visits).

In patients who have presented acute renal failure with hospitalization, monitoring of renal function will be required for at least two years, even if renal function has returned to baseline.34

In any case, it is necessary to individualize these general criteria.

In each clinical visist to the family doctor it is recommended:

• -

  Control BP and adjust the treatment. BP target < 140/90mmHg (using self-measurement of BP at home). Try to reach BP values of 130/80mmHg, if it is tolerated, in patients with UACR>30mg/g and especially in those with values > 300mg/g. Avoid a reduction of systolic BP below 120mmHg, especially in elderly patients, if orthostatic hypotension or autonomic neuropathy are present.68 Treatment should be individualized according to tolerability and the impact on renal function and electrolytes.69

• -

  Monitor the presence of renal anemia: If CKD 3-5 and Hb < 10.0g/dL (after ruling out iron deficiency: IST>20 % and ferritin > 100ng/mL), consider referral or and earlier follow-up visit in Nephrology to evaluate treatment with erythropoiesis-stimulating factors according to the established protocols.63

• -

  Review the medication, adjusting the dose according to the GFR (oral antidiabetics of renal elimination, direct-acting oral anticoagulants). In CKD 3-5, avoid the use of NSAIDs and iodinated contrast agents.

• -

  Review dietary habits, recommending appropriate physical exercise for each age and clinical situation, achieving the ideal weight, as well as quitting smoking and guiding the patient on the type of diet to follow according to the GFR:

  • o

    CKD 1-3: Moderate sodium restriction is only recommended in the case of hypertension or volume overload.7

  • o

    CKD 4-5: Dietary recommendations for moderate sodium, potassium, phosphorus and protein restriction (0.8g/kg/day).

• -

  Laboratory tests in each follow-up visit for patients with CKD G3 or more advanced CKD* (in italics the minimum recommended):

  • o

    Complete blood count

  • o

    Serum concentration of glucose, creatinine, urea, sodium, potassium, calcium, phosphate, albumin, cholesterol, triglycerides, and urate. eGFR by CKD-EPI-creatinine.

  • o

    UACR in the first morning urine sample.

  • o

    Urine sediment.

• -

  Review criteria for referral to nephrology in teach of he follow-up visits.

* Efforts will be made to combine the request for laboratory tests with other specialties or with Primary Care so as not to repeat them.

Table 11 shows the objectives in the monitoring and follow-up of patients with CKD according to stages.

Once the patient is diagnosed with CKD, the priority is to prevent progression of of CKD by acting on the renal progression factors and be aware that there are drugs used in daily practice that are nephrotoxic and may cause progression of CKD (Table 7).

The initiation, evolution and prognosis of CKD is influenced by various risk factors that are frequently present in the general population.73 The recommendations in this regard are as follows:

• •

  Physical exercise: 30-60minutes of moderate exercise is recommended, 4 to 7 days per week (minimum of 150min/week), with moderate-intensity aerobic and/or strength exercises to avoid a sedentary lifestyle and with individualized programs based on the patient's characteristics and a gradual introduction in time and intensity.74

• •

  Diet: Mediterranean-type, with foods rich in fiber, avoid saturated and trans fats and individualize according to existing risk factors, low sodium diet 6g of salt (equivalent to 2.4g sodium) in case of hypertension and/or heart failure.75 There is controversy regarding potassium restriction in CKD, especially in patients who do not have hyperkalaemia, since some studies have shown that diets with moderate or high potassium content can reduce kidney damage,76 but the important point is to establish strategies to avoid severe hyperkalemia. In advanced phases of CKD (G4-G5) will be recommended dietary content of sodium, phosphorus, potassium and proteins. In patients with CKD G4-G5 not on dialysis it is recommended protein restriction of 0.8 is g/kg/day (at least half must be animal proteins of high biological value).77 In patients with CKD on hemodialysis, protein intake may be increased to 1.2g/kg of weight to favor an adequate protein balance and avoid caloric-energy wasting and maintain an adequate nutrition.78,79

• •

  It is recommended to avoid alcohol intake above 12-14grams/day (approximately 300 cc of beer or 150 cc of wine), and to avoid smoking due to its deleterious cardiovascular and renal effects.80–83 The issue of staying away from tobacco consumption should be discussed in all the clinic visits. Empathetic, firm and motivated advice will be given to smokers to quit smoking using Systematized Minimum Intervention, cognitive-behavioral techniques or pharmacological treatment (bupropion at lower doses than usual –150mg/24h in advanced stages of CKD, or varenicline at usual doses or reduced to half (1mg/24h) in patients with decreased renal function (CKD G4 and G5).

Dyslipidemia increases cardiovascular risk therefore control of lipids is an objective in patients with CKD. Dyslipidemia is considered to be of high (GFR 30-59mL/min/1.73m 2) or very high cardiovascular risk (GFR<30mL/min/ 1.73m2 ). The suggested LDL-c targets are a ≥ 50% reduction as compared to baseline and, values of 70mg/dL in CKD G3 and 55mg/dL in CKD G4.108

There is evidence of the benefit of treating dyslipidemia in CKD in stages prior to dialysis (G5D),109 but the benefits in dialysis patients are not so clear.

Treatment will be based on dietary measures and the administration of statins alone or associated with ezetimibe.110 Ezetimibe does not require dose adjustment for renal insufficiency. The statins of choice would be those with hepatic removal (fluvastatin, atorvastatin and pitavastatin). In the case of kidney transplant patients, certain interactions must be taken into account,111 particularly between cyclosporine and atorvastatin, lovastatin, and simvastatin, since it can increase their levels and therefore the risk of myopathy. Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are less likely to present interactions. Although tacrolimus is also metabolized by CYP3A4, it seems to have less risk of interacting with statins. In these patients, statins should be started at low doses, titrated cautiously, and monitorinteractions.112

Being the control of cholesterol the primary objective, the KDIGO113 guidelines recommend the use of fibrates with triglyceride concentrations > 1,000mg/dL to avoid pancreatitis. Changes in lifestyle are recommended if values > 500mg/dL. In the case of association with statins, fenofibrate is preferred to gemfibrozil due to the lower risk of myopathy and rhabdomyolysis and the dose should be adjusted to the renal function (67-100mg/24h if the GFR is between 30-60mL/min/1.73m 2). However, it is expected to observe a decrease in GFR of still uncertain significance, probably related to the inhibition of tubular secretion of creatinine, increased production of creatinine by fibrates or an increase in vasodilator prostaglandins, resulting in a false decrease in GFR.114

There is no evidence in the general population on the use of Omega 3 fatty acids for the treatment of dyslipidemia115 and no studies in CKD that support their use.

The inhibitors of Proprotein convertase subtilisin/kexin type 9 (PCSK9) may be an alternative in patients with CKD who have not responded to other treatments and have had previous cardiovascular events. Evolocumab and alirocumab have shown their ability to reduce the levels of LDL cholesterol with a reduction of major cardiovascular events in secondary prevention in patients with high or very high cardiovascular risk in the FOURIER and ODYSSEY-OUTCOMES studies.116,117 It has been published one study on efficacy and safety in patients with CKD included in the FOURIER study. The results of such study show that these patients present a reduction in major cardiovascular events similar to those with normal renal function, and do not present a higher rate of adverse events or changes in renal function, except for patients who develop rhabdomyolysis.118 None of these studies has been specifically designed for patients with CKD. In addition, patients with GFR below 20mL/min/1.73m 2 and transplant patients were excluded. However, the Spanish Society of Atherosclerosis recommends treatment with PCSK9i in primary prevention in patients with CKD grade 3b or higher if they do not achieve LDL cholesterol <130mg/dL with statins.119 The indication of these drugs in our country is subject to the therapeutic positioning report.120,121

Until now, RAAS blockade had been the only evidence in the treatment and prevention of CKD, both in diabetics and in non-diabetic patients.7,68,89,122,123 In DM-2, treatment with SGLT2-i has, to date, the greatest evidence of nephroprotection36,37,100,101,124 and there is also evidence of a reduction in albuminuia with GLP-1 RAs.125–127

Recently finerenone, a more specific and selective mineral corticosteroid receptor antagonist without hormonal effects and with less tendency to hyperkalaemia than spironolactone and eplerenone, has shown nephroprotective benefit when compared with placebo in DM-2 patients treated with iRAAs. Finerenone is not marketed at the moment.128

The DAPA-CKD study has shown the benefit of an SGLT2-i (dapagliflozin) not only in diabetics but also in non-diabetic patients, including IgA nephropathy.124,129

Based on this study, dapagliflozin has recently been indicated not only for diabetic kidney disease but also for non-diabetic kidney disease patients, being able to be maintained until eGFR of 25mL/min/1.73m2. Likewise, the data sheet for empagliflozin has recently been modified, and it can be started with eGFR>45mL/min/1.73m 2, and it can be used in diabetics and non-diabetics with heart failure and with eGFR > 20mL/min/1, 73m2. Therefore the SGLT2-i can be used even in reduced GFR, each one with its specific characteristics indicated in their technical data sheets. The development of new studies will probably lead to a broadening of the spectrum of indications for these drugs and even in greater ranges of eGFR.

Obesity is a factor of renal progression and should be considered as a target to be treated to reduce cardiovascular risk and CKD progression.130 It is a paradox to observe an inverse relationship between obesity and mortality in dialysis patients and it seems that a high BMI protects in the short term, but this benefit is not maintained over time.131

There is no solid evidence on treatments for obesity in CKD. Liraglutide, a GLP1 RA, is currently available and, according to the data sheet, is indicated for the treatment of obesity in combination with a low-calorie diet and increased physical activity. Its mechanism of action includes delayed gastric emptying and a central action decreasing appetite, so it increases the feeling of satiety. The GLP-1 RAs marketed in our country that have shown renal benefits (liraglutide, semaglutide, and dulaglutide) can be administered with GFR of 15mL/min/1.73m2.132 Pharmacokinetics studies indicate that in CKD G5 it does not increase the area under the curve, not even in dialysis patients. But there are no studies to support its use in CKD G5.

Hyperuricemia may produce a variable clinical spectrum: acute gouty arthritis due to the precipitation of monosodium urate crystals in the joints, tophaceous gout due to the precipitation of crystals in the skin and subcutaneous cellular tissue, uric nephrolithiasis, Acute uric acid nephropathy and chronic uric acid nephropathy.

Currently there is not sufficient evidence for the treatment of asymptomatic hyperuricemia. Decisions to initiate treatment will be based on each patient's risk of developing crystal deposits, gout, or uric acid nephropathy, as well as treatment-related side effects. The decision regarding the establishment of lifestyle-based or pharmacological therapies for asymptomatic hyperuricemia should be individualized based on estimates of the risk of hyperuricemia-related clinical events and the potential benefits and risks of the intervention.

Uric acid-lowering drugs include: a) xanthine oxidase (XO) inhibitors that block purine metabolism, b) uricosurics that act on the main cause of hyperuricemia, which is low renal excretion, and 3) treatment with uricase which oxidizes urate, through an enzymatic reaction, to allantoin. It is recommended to start treatment with urate-lowering drugs after the first attack of gout in patients with CKD≥G2. The goal is to keep uric acid levels below 6mg/dL (5mg/dL in tophaceous gout).

Table 13 includes a list of the different urate-lowering drugs marketed in Spain, their mechanism of action and dose for the different CKD stages.

Regardless of each of the uric acid-lowering drug, there are common rules in the use of all of them: a) always start treatment with prophylaxis, b) start with the lowest dose and monitor the levels until the target is reached, c) the drug should not be withdrawn or its dose modified during a gout attack, and 4) in the case of a new treatments, the drug should be introduced after the resolution of the acute gout attack. The guidelines recommend prophylactic treatment for three months or six months in cases of tophaceous gout when hypouricemic agents are started. Colchicine is contraindicated in patients with a GFR less than 30mL/min/1.73m 2, and in patients with CKD stage 3 the patients should receive a 0.5mg tablet daily.

Table 14 shows the drugs that can be used during an acute attack of gout and their dose adjustment in patients with CKD.133

Anemia associated with CKD is generally normocytic and normochromic and is not usually associated with iron deficiency (ferritin > 100ng/mL and IST>20%). Otherwise, it is advisable to make a differential diagnosis with other causes of anemia. Nevertheless, anemia of renal cause is a diagnosis of exclusion.

In the presence of anemia in a patient with CKD, other causes of anemia should to rule out, a study should be performed including: complete blood count, percentage and count of reticulocytes, ISAT, ferritin, B12 and folic acid.63

The indications for the referral of a patient with CKD and anemia will be63 :

• o

  Indication of intravenous iron therapy (failure/intolerance of oral iron therapy).

• o

  Indication for treatment with ESA-EPO.

• o

  In the patient treated with ESA-EPO and confirmed Hb ≥ 13g/dL or Hb ≤ 9g/dL (for dose adjustment).

These aspects are specified in more detail in the consensus document for the detection and management of renal anemia by the SEN and the three societies family physicians.63

Alterations in calcium and phosphorus metabolism in CKD are associated with various complications that go beyond simple bone involvement (previously called renal osteodystrophy) involving other systems, especially the cardiovascular system (for example, vascular and valvular calcifications, arterial stiffness, left ventricular hypertrophy, etc.), clearly associated with an increase in cardiovascular and global morbidity and mortality.

The best known clinical manifestation is the increase in parathyroid hormone (PTH) [(secondary hyperparathyroidism (SHPT)] produced, among other factors, by a multifactorial tendency to hypocalcaemia, a deficiency of active vitamin D (calcitriol) or the retention of phosphate (with or without hyperphosphatemia). In fact, it is common to find normal plasma levels of calcium and phosphorus at the expense of a significant elevation of PTH, so they should always be assessed as a whole.134,135 The appearance of hypercalcemia and / or hypophosphatemia with elevated PTH, in these cases primary hyperparathyroidism (parathyroid hyperplasia or adenoma) should be considered, even in patients with CKD The management of hyperparathyroidism secondary to CKD is carried out by Nephrology.

The goals of screening and treatment are:

• o

  Avoid hyperphosphatemia

• o

  Avoid vitamin D deficiency (calcidiol or 25-OH-vitamin D)

• o

  Avoid persistent and progressive increase in SHPT

Hyperphosphatemia should be initially treated with an adequate and balanced diet (with special care to reduce the intake of inorganic phosphorus contained, for example, in the additives of prepared foods) and/or with the use of phosphate binders.134,135 Serum vitamin D concentration should be corrected to at least 20-30ng/mL (50-75nmol/L) by supplementation that will contribute to the pleiotropic hormonal actions of vitamin D and control mild cases of HPS.

Especially in stages G4 and G5, it is even recommended to maintain PTH at values slightly above normal, so that intact PTH levels classically considered adequate in a patient with CKD G5 are between 150-300 pg/ml (two to five times the upper limit of normal for the assay used). A small degree of stable SHPT is not worrisome and represents an adaptive phenomenon (ie PTH is a phosphaturic hormone), but progressive SHPT, with PTH values two or three times higher than the reference value despite adequate levels of calcidiol, they could require at least an initial consultation with a Nephrology specialist and/or the initiation of active forms or analogs of vitamin D (calcitriol, paricalcitol, alfacalcidol). Persistently high phosphate levels would also be worthy of dietary advice and/or nephrology consultation.

Treatment is based on:

• o

  Dietary advice to avoid hyperphosphatemia.

• o

  Phosphate binders or binders: calcium carbonate, calcium acetate or its association with magnesium, sevelamer (hydrochloride or carbonate), lanthanum carbonate or sucroferric oxyhydroxide.

• o

  Native” vitamin D (cholecalciferol or calcifediol).

• o

  In case of persistence and especially progression of HPS (trends are assessed), calcitriol or vitamin D analogues.136 Calcimimetics can be used in dialysis patients.

Osteoporosis has recently gained relevance as an added problem in patients with CKD. It can be senile, postmenopausal or associated with steroid treatment, among other causes. In addition, it is now known that the frequency of fractures and their morbidity and mortality are higher in patients with CKD137 and that densitometry (DEXA) has a predictive value for fractures in these patients as well. Densitometry would be indicated if the results impact therapeutic decision-making. There is no clear evidence on the treatment of osteoporosis in CKD and there are only retrospective experiences that these drugs are effective in patients with CKD.138,139 However, current guidelines advise adopting an active attitude in this regard.134,140

Hyperkalemia is defined as a serum potassium concentration above the upper limit of normal (5 mEq/L). It is considered mild hyperkalaemia if potassium concentrations are between 5 and 5.5 mEq/L, moderate between 5.5 and 6 mEq/L, and severe if it is greater than 6 mEq/L. Hyperkalaemia is generally associated with a decrease in GFR (reduced ability to excrete potassium), the use of iRAAs and/or MRA, or abnormal redistribution of potassium (intra-extracellular). An important exception is hyporeninemic hypoaldosteronism (type IV renal tubular acidosis) in whom hyperkalaemia may occur with moderate reduction in GFR. These are characterized by hypoaldosteronism and hyperkalemia and it may be present in various types of kidney diseases such as diabetic nephropathy, interstitial nephropathy and obstructive uropathy, as well as with the use of NSAIDs, among other causes.

Cation exchange resins remove potassium by an exchange for another cation in the GI tract. Its main drawback is its limited effectiveness and the delay in the onset of its action that could be of several hours, in addition it produces GI intolerance. Recently, two new potassium chelating agents have been developed (patiromer and sodium zirconium cyclosilicate), which offer better tolerance and efficacy. The chronic use of these new drugs may allow the maintenance of the cardio-renal benefit of iRAAS with much better tolerance than the classic calcium polystyrene sulfonate.

The measures for the treatment of asymptomatic moderate-mild hyperkalemia are shown in Table 15. More details on the treatment of chronic hyperkalemia can be found in the following publication.141

Metabolic acidosis in CKD is usually a chronic normochloremic acidosis or with an increased anion gap that frequently appears if the GFR<20mL/min/1.73m 2 due to an increased acid load due to the renal inability to eliminate them. It is important to treat it to avoid long-term bone demineralization, as well as the progression of CKD itself, among other deleterious effects.142

Oral sodium bicarbonate can be used if blood bicarbonate is less than 22mmol/L.7 There are also other measures such as diets rich in plant-based proteins that produce bases such as fruits and vegetables143 and other recently marketed drugs such as veverimer, a non-absorbable polymer that binds selectively to hydrochloric acid, eliminating it from the intestinal lumen through through feces.144 Obviously, sodium overload induced by classic bicarbonate should be avoided, as well as overcorrection and metabolic alkalosis.

The HCV infection is associated with a 23% increased risk of CKD development and progression, the hidden mechanisms of this association are currently under investigation.145

The different guidelines and scientific societies, including the Strategic Plan for the Management of Hepatitis C 2015 recommend antiviral therapy for all patients with chronic hepatitis due to HCV with CKD with/without RRT, including candidates to kidney transplant. The only exception is patients with specific contraindications or with limited life expectancy due to other intercurrent diseases. There are no recommendations for the management of acute hepatitis C.146,147

Treatments based on interferon and ribavirin have been poorly tolerated as they are eliminated by the kidney and have significant side effects, with a low rate of sustained viral response.

Direct-acting antivirals achieve a sustained viral response greater than 90-95%, presenting an excellent safety and tolerance profile.148–150 Adverse effects are infrequent, but and interactions with commonly used drugs are very common, to be taken into account especially in renal transplant recipients.151

The current regimens with greater efficacy and safety for patients with advanced CKD or on dialysis, free of interferon, include: elbasvir/grazoprevir (genotypes 1 and 4), ombitsavir/dasabuvir/paritaprevir/ritonavir (genotype 1), ledipasvir/sofosbuvir (genotypes 1, 4, 5, and 6), glecaprevir/pibrentasvir, and sofosbuvir-velpatasvir (all genotypes).152–154 In some cases it is necessary the administration of ribavirin.

Achieving sustained viral response or undetectable viral RNA level after 12-week treatment is considered cure in 99% of patients with long-term follow-up. However, a second viral RNA determination is required during the first year after completion of therapy.146

The prevalence of atrial fibrillation (AF) is significantly increased in subjects with CKD and HD, and cardioembolic strokes is one of the most frequent complications.155 Patients with AF and CKD are at increased risk of thrombotic complications due to the frequent coexistence of other factors such as advanced age, DM, vascular comorbidities, or RRT itself. However, hemorrhagic events are also very frequent, as a consequence of the alteration in the generation, activation and function of platelets in kidney patients.156

There are different DOACs approved for the prevention of stroke in patients with AF. They act through the inhibition of factor Xa (rivaroxaban, apixaban, edoxaban), or thrombin (dabigatran).

An important aspect to consider is that the recommendations of the pivotal studies with DOACs have been made based on the use of the C&G formula and not CKD-EPI. Although scientific societies recommend the latter equation, for the time being the prescription should be based on C&G, since this is what the dosage was based on in the pivotal studies. The scientific societies must pronounce themselves in this regard.

In pivotal clinical trials, DOACs achieved non-inferiority criteria as compared to warfarin in patients with creatinine clearance (CrCl) (calculated using the C&G equation) of 30-50mL/min (20-50mL/min in the case of apixaban). However, there is not enough evidence to recommend one DOAC over the others, since no trials have been carried out to compare some drugs with others.

Although the efficacy in the prevention of stroke and systemic embolism may be non-inferior to warfarin, the overall safety profile of DOACs is superior to vitamin K antagonists (VKAs). In all pivotal trials, DOACs have been associated with significant reductions (about 50%) in the risk of intracranial hemorrhage compared with warfarin.

Anticoagulant treatment in patients with CKD according to CrCl:

• o

  CrCl >50mL/min: The decision to anticoagulate these patients with non-valvular AF should be based on clinical trials, and in these cases DOACs are superior to VKAs that in Spain are dicoumarins.

• o

  ClCr between 15-30mL/min: In these patients, anticoagulation will be assessed considering the risk/benefit of the treatment.

• o

  CrCl<fifteen mL/min: There is insufficient evidence from clinical trials to support anticoagulation in these patients. Some trials have shown benefit from the use of DOACs in these patients. The use of anticoagulant treatment and the type of pharmacological treatment or closure of the left atrial appendage by endovascular procedure, should be decided on an individual basis. In this group of patients and in those on dialysis, the use of DOACs versus VKAs should be considered when there is calciphylaxis, risk of relevant vascular calcification, or a history of warfarin-induced nephropathy, and always making an appropriate dose adjustment.156,157 There are everal clinical trials underway testing DOACs in this population that will provide us with answers about the treatment needs in this very high-risk population.

Table 16 shows the current recommendations for the administration of DOACs in CKD.158

Table 16.

Characteristics of the different direct acting oral anticoagulants (DOACs) (dosage in CKD, metabolism and elimination by dialysis). Modified from references.156–158

• o

  Control of cardiovascular risk factors and monitoring variables that favor CKD progression, especially BP, body weight and blood glucose.

• o

  Monitoring nephrotoxicity to avoid iatrogenesis in any process, paying special attention to:

  • -

    Avoid the use of NSAIDs whenever possible.

  • -

    Avoid hyperkalaemia associated with the use of drugs.

  • -

    Avoid/adapt the use of oral antidiabetics according to GFR.

  • -

    Avoid as much as possible the use of iodinated contrast agents, adjusting any drug to the patient's GFR.

  • -

    In the event of a deterioration in renal function, always rule out functional causes (excessive control of blood pressure, NSAIDs, volume depletion) before referring to Nephrology.

• o

  Participation in therapeutic compliance and referral to Nephrology in case of unexplained acute worsening of renal function or the presence of complications.

• o

  Follow-up of elderly patients, with stable GFR, who, for reasons of age, quality of life or others, are not eligible for RRT and do not receive erythropoiesis-stimulating agents (ESAs) and/or complex medication for SHPT of CKD.

• o

  In the case of dialysis patients, learn about the different options of dialysis technique and their implementation (place to perform the dialysis, periodicity, structural needs and possible complications), especially the techniques that the patient performs at home. The family doctor plays especial role in the management of the dialysis patient who, for reasons of clinical deterioration and after a consensus decision, it is decided to withdraw dialysis treatment and provide his care al home.

• o

  In the case of kidney transplant patients, in addition to knowing the types and their peculiarities, immunosuppressive treatment is of special interest due to the complications, side effects and interactions that may occur.

• o

  When a patient opts for conservative management of their CKD, we will continue to actively treat the complications that may occur throughout its evolution (anemia, hyperkalaemia, metabolic acidosis) until reaching the terminal phase of uremia, working in a coordinated manner: Nephrologist, Family doctors, Home Care and palliative care if required.

• o

  Ensure and participate actively in the vaccination of patients with CKD159 :

  • -

    General recommendations: tetanus (complete five doses, dose received, dose that counts), triple viral (two-dose regimen, if not previously vaccinated) and varicella-zoster virus if susceptible (two intramuscular doses separated by two to six months).

  • -

    Specific recommendation: Annual flu. Pneumococcus (VNP23 sequential pattern+PCV13) if the patient has not been vaccinated 1 °PCV13 and at 12 months VNP23 (accelerated regimen only wait two months), if vaccinated with PCV23 wait 12 months to administer PCV13. Hepatitis B (vaccine of 40μg HBsAg, regimen: 0, 1 and 6 months). Perform serological control at four to eight weeks to verify seroconversion. Booster dose if in annual follow-up anti-HBs are <10 mIU/mL and also vaccination against COVID-19.

• o

  Maintain communication between the family doctor and Nephrology using all means that technology offers us, all in a virtual manner:

  • -

    Via telephone: with pre-established schedules and direct pone calls.

  • -

    Via the Internet: specific consultations such as "telenephro", intranephro, etc. The family doctor would refer doubts, queries about specific patients and the nephrologist would respond in less than 24-48hours about the strategy to follow.

  • -

    Videoconferences, about specific consultations or online training.

• o

  Maintain continuing medical education in collaboration with Nephrology on the following issues:

  • -

    Control of cardiovascular risk factors.

  • -

    Follow-up and monitoring of patients with CKD. Preferably assess the GFR and evaluate the presence of albuminuria in urine, to classify the patient's risk.

  • -

    Recognize the different stages of kidney function loss and understand the criteria for referral to Nephrology.

  • -

    Prevention of nephrotoxicity and avoid iatrogenesis, especially in polymedicated elderly patients.

To avoid delays in referrals to appropriate specialists, certain pathologies that are listed that should not be referred to Nephrology.

• •

  Urological pathology:

  • o

    Renal colic/renal lithiasis.

  • o

    Simple renal cysts (do not refer), or complex cysts (Bosniak IIF, III and IV: refer to Urology).

  • o

    Urinary tract infections with normal renal function.

  • o

    Renal tumors/masses.

• •

  Non-urological pathology:

  • o

    Non-renal anemia.

  • o

    Primary hyperparathyroidism with normal renal function or secondary to vitamin D deficiency.

There are factors that accelerate renal deterioration regardless of the specific rate of progression of CKD. Since many of these factors are reversible, it is essential to recognize and correct them.

General measures:

• 1)

  Hydration: abundant fluid intake should not be recommended in all patients with CKD. It is important to limit salt intake. Adequate fluid intake must be ensured, especially in elderly patients and in the summer time, but this recommendation must be applied with caution and should be individualized. It is not applicable to patients with cardiorenal syndrome, at risk of hydrosaline retention and congestive heart failure.

• 2)

  A low-potassium and protein-restricted diet should not be generalized to all patients with CKD. It should be individualized according to laboratory results, aetiology, symptoms and individual characteristics of each patient.

• 3)

  Referral to Nephrology: a CKD patient should not be diagnosed with a single measurement of creatinine, GFR and/or albuminuria.

• 4)

  The presence of kidney injury markers is essential to classify a CKD patient if their GFR is > 60mL/min/1.73m 2.

Pharmacological interventions:

Drugs should not be used without adjusting the dose to the GFR. In general, the most important recommendations are the following:

• 1)

  NSAIDs: should be avoided at any stage of kidney disease, although occasional use may be necessary in certain situations.

• 2)

  RAAS:

  • •

    Double RAAS blockade with ACE inhibitors associated with ARBs or direct renin inhibitors is not recommended in diabetic and/or CKD patients.

  • •

    RAAS should not be discontinued if there is a slight increase in creatinine with the corresponding decrease in GFR. After introducing the drug, the serum creatinine should be monitored 7 to 10 days thereafter; elevations of up to 20-30% are tolerable, given its antiproteinuric/cardio and nephroprotective benefits.

  • •

    Do not suspend these drugs if there is a slight-moderate increase in serum potassium. Hyperkalaemia should be treated with dietary and pharmacological measures, avoiding the suspension of the drug that offers cardio and nephroprotective benefits.

  • •

    Only suspend treatment with these drugs in patients with infectious or acute gastrointestinal processes that involve dehydration or hypotension, trying to reintroduce them slowly after recovery.

  • •

    Do not administer RAASi to patients with bilateral renal artery stenosis (which is rare), or with severe diffuse distal renal vascular lesions, as they may reduce GFR markedely (>30%).

• 3)

  Diuretics:

  • •

    The use of thiazide diuretics is not recommended in patients with moderate-advanced CKD. In these situations, loop diuretics (furosemide, torasemide) should be used preferably. Thiazide diuretics are generally ineffective with GFR<30mL/min/1.73m 2. They could be associated with loop diuretics, in patients with cardiorenal syndrome and episodes of heart failure, with hydrosaline retention, in whom a potentiation of the diuretic effect is observed.160

  • •

    The uncontrolled use of AMR (spironolactone, eplerenone) is not recommended in patients with moderate-advanced CKD due to the risk of hyperkalaemia. If indicated to treat heart failure with reduced ejection fraction or in patients with resistant hypertension, with normal values of potassium, it should be started with low doses and with frequent monitoring of serum potassium concentration. Special attention should be paid in periods of exacerbation.

• 4)

  Digoxin should not be administered without dose adjustment according to the GFR especially in patients with GFR less than 30mL/min/1.73m 2.

• 5)

  Fibrates associated with statins should not be administered in patients with CKD stage G3b -G5 (GFR<45mL/min/1.73m 2).

• 6)

  No antibiotic should be given without adjusting the dose for the stage of CKD.

• 7)

  Do not administer antidiabetic drugs without taking into account the stage of CKD and modify te dose if when there are changes in FGFR.

• 8)

  Radiological contrast agents: As far as possible, the administration of iodinated contrast agents should be avoided in patients with CKD G3b -G5 (GFR<Four. Five mL/min/1.73m 2). Risk-benefit should always be weighed. If the administration of contrast agents is essential, we should recommend adequate volume replacemet of the patient, suspension of metformin in diabetics, avoid diuretics whenever possible, correcting metabolic acidosis by administering sodium bicarbonate and also give of N-acetylcysteine (600mg the day before and the day of the radiological test). Avoid magnetic resonance imaging with gadolinium in patients with CKD with GFR<30mL/min/1.73m 2 because of the risk of developing nephrogenic systemic fibrosis.

• 9)

  Do not use intestinal preparations rich in phosphorus to perform colonoscopy.

Dr. Rafael García Maset declares that he has received fees for lectures from Amgen, Boehringer-Ingelheim, Esteve and Fresenius Medical Care, not related with present work.

Dr. Jordi Bover Sanjuán declares that he has received honoraria for lectures and consultancies from Abbvie, Amgen, Rubió, Sanofi and Vifor Pharma, not related with present work.

Dr. Julián Segura de la Morena declares that he has received fees for conferences from AstraZeneca, Esteve and Medtronic, not related with present work.

Dr. Marian Goicoechea Diezhandino declares that she has received conference and consultancy fees from Astellas, AstraZeneca, Boehringer-Ingelheim, Novonordisk, Sanofi and Vifor Pharma, not related with present work.

Dr. Javier Escalada San Martin declares that he has received conference fees from AstraZeneca, Boehringer-Ingelheim, Lilly, Mundipharma and Novonordisk, not related with present work.

Dr. Lorenzo Fácila Rubio declares that he has received fees for lectures from AstraZeneca, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo and Pfizer, not related with present work.

Dr. Lisardo García-Matarín declares that he has received fees for conferences and consultancies from AstraZeneca, Bial, Boehringer-Ingelheim, GlaxoSmithKline, Menarini, Novartis, Novonordisk, Pfizer, Sanofi, Teva and Vifor Pharma, not related with present work.

Dr. María Isabel Gutiérrez Pérez declares that she has received conference fees from GlaxoSmithKline, not related with present work.

Dr. Pilar Mazón Ramos declares that she has received fees for conferences and consultancies from AstraZeneca, Boehringer-Ingelheim, MSD and Novonordisk, not related with present work.

Dr. Manuel Muñoz Torres declares that he has received conference fees from Amgen, Lilly and Novonordisk, not related with present work.

Dr. Manuel Pérez-Maraver declares that he has received fees for conferences and consultancies from Abbot, AstraZeneca, Lilly, Novonordisk and Sanofi, not related with present work.

Dr. José Luis Górriz Teruel declares that he has received fees for conferences and consultancies from AstraZeneca, Boehringer-Ingelheim, Lilly, Mundipharma, Novartis, Novonordisk and Vifor Pharma, not related with present work.

Drs. Jesús Cebollada del Hoyo, Javier Gamarra Ortiz, Jose A. García-Donaire, Sílvia Gràcia Garcia, Julio Hernández Moreno, Rosario Montañés Bermudez, Pedro de Pablos-Velasco, Carmen Suárez Fernández and Salvador Tranche Iparraguirre declare that they have no conflict of interests.