szmtag The Management of Non–Dialysis-Dependent Chronic Kidney Disease in Primary Care (30.10.2020)
DÄ internationalArchive44/2020The Management of Non–Dialysis-Dependent Chronic Kidney Disease in Primary Care

Clinical Practice Guideline

The Management of Non–Dialysis-Dependent Chronic Kidney Disease in Primary Care

Dtsch Arztebl Int 2020; 117: 745-51. DOI: 10.3238/arztebl.2020.0745

Weckmann, G; Chenot, J; Stracke, S

Background: Approximately 10% of adults in Germany have chronic kidney disease (CKD). The prevalence of CKD among patients being cared for by general practitioners is approximately 30%, and its prevalence in nursing homes is over 50%. An S3 guideline has been developed for the management of CKD in primary care.

Methods: The guideline is based on publications retrieved by a systematic search of the literature for international guidelines published in the period 2013–2017, and additional searches on specific questions. It was created by the German College of General Practitioners and Family Physicians (Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin, DEGAM) and consented with the German Societies of Nephrology and Internal Medicine (DGfN, DGIM) and patient representation.

Results: Upon the initial diagnosis of CKD (glomerular filtration rate [GFR] <60 mL/min), the patient’s blood pressure and urinary albumin-to-creatinine ratio (ACR) should be measured, and the urine should be examined for hematuria. Monitoring intervals are determined on an individual basis depending on the stage of disease and the patient’s general state of health and personal preferences. Nephrological consultation should be obtained if the GFR is less than 30 mL/min, if CKD is initially diagnosed (GFR 30–59 mL/min) in the presence of persistent hematuria without any urological explanation or of albinuria in stage A2 or higher, if the patient has refractory hypertension requiring three or more antihypertensive drugs, or if the renal disease is rapidly progressive. The threshold for referring a patient should be kept low for persons under age 50; persons over age 70 should be referred only if warranted in consideration of their comorbidities and individual health goals.

Conclusion: The main elements of the treatment of CKD are the treatment of hypertension and diabetes and the modification of lifestyle factors. An innovation from the primary care practioner’s perspective is the assessment of albuminuria with the albumin-to-creatinine ratio.

LNSLNS

The prevalence of chronic kidney disease (CKD) continues to rise worldwide; in the German adult population, it is quoted as being between 10% and 13% (1, 2, 3, 4, 5). In the primary care setting, CKD is more common than in the general population. Up to 27% of patients in primary care have CKD; in nursing homes the prevalence is even higher with over 50% of the residents having the disease (6), while dialysis-dependent CKD is rare (7). Most patients have early CKD stages and in many patients kidney function remains stable over several years. A British study found that after five years the kidney function of patients with CKD stages G3 to G5 receiving primary care was stable in about 50% and had improved in 25% to 30% of cases, while the disease progressed in 10% to 15% (8). Nevertheless, with approximately 93 000 dialysis-dependent patients, progression to end-stage renal disease is a relevant public health problem in Germany (9). The need to adapt medication and dosing in patients with CKD and the avoidance of polypharmacy are also critical. The key risk factors for CKD are diabetes and hypertension, both of which are also increasing in prevalence. The majority of patients with CKD are geriatric patients with age-related impairment of renal function in the early CKD stages. Only a small proportion is younger than 60 years or experiences severe impairment of kidney function (8).

In 2019, the German College of General Practitioners and Family Physicians (DEGAM, Deutsche Gesellschaft für Allgemeinmedizin) issued the clinical practice (S3) Guideline on the Management of Non-dialysis-dependent Chronic Kidney Disease in Primary Care (10). The DEGAM guideline is based on a systematic review of international evidence-based guidelines (11) and consented with the German Society of Nephrology (DGfN, Deutsche Gesellschaft für Nephrologie) and the German Society of Internal Medicine (DGIM, Deutsche Gesellschaft für Innere Medizin) and patient representation.

The aim of the new guideline is to provide physicians with evidence-based recommendations on the prevention, screening and management of chronic kidney disease. Another concern is to prevent over-diagnosis and over-treatment.

Method

In preparation of the guideline, key questions were consented with general practitioners/family physicians and nephrologists in a Delphi process (eTable 1, eBox).

Contributors to the development of the guideline
eBox
Contributors to the development of the guideline
Key questions
eTable 1
Key questions

A systematic literature search was conducted to identify relevant evidence-based guidelines. Its search strategy is detailed in the eMethods section. The methodological quality of the source guidelines was assessed using the AGREE II instrument. Relevant recommendations were extracted and adapted to reflect the German health care system (11).

If no relevant guideline recommendation was available for a specific question, a targeted de-novo literature search was conducted.

Results

In three Delphi rounds, 23 key questions were consented (eTable 1). From the 1274 citations retrieved, nine evidence-based guidelines with relevance for outpatient care in Germany were identified (eFigure).

Flowchart of the results of the systematic search and selection of the literature CKD, chronic kidney disease; HIV, human immunodeficiency virus
eFigure
Flowchart of the results of the systematic search and selection of the literature CKD, chronic kidney disease; HIV, human immunodeficiency virus

The guidelines of the National Institute of Health and Care (NICE) and Kidney Disease: Improving Global Outcomes (KDIGO), both of which achieved a score of >80%, were selected as the primary source guidelines for the adaptation of the recommendations to the German health care system (eTable 2, eMethods) (11).

Assessment of the methodological quality of the guideline using the AGREE-II instrument
eTable 2
Assessment of the methodological quality of the guideline using the AGREE-II instrument

The guideline was created based on the consented key questions, with the adapted recommendations serving as answers.

Guideline recommendations

Definition of chronic kidney disease (CKD)

From the KDIGO guideline, the CKD categories G1 to G5, based on the glomerular filtration rate (GFRcreatinine), and the albuminuria categories A1 to A3, based on the spot urine albumin-to-creatinine ratio (Table 1, Table 2), were adopted (12). To verify the chronicity of renal impairment, serum creatinine levels and urine ACR should repeatedly be measured at 3-month intervals. A CKD is diagnosed if GFR is <60 mL/min or ACR >30 mg/g creatinine in spot urine. The CKD G1–G2 categories only support a diagnosis of CKD if they are combined with albuminuria or structural abnormalities of the kidneys. GFR is commonly calculated indirectly from creatinine (eGFR, estimated GFR). The frequency with which a misclassification occurs as the result of a problem with the measuring method can be considered as low compared to clinical causes. The globally applicable definition of CKD does not include cystatin C, urea and uric acid (12). Compared to creatinine, the cost of measuring cystatin C is very high; consequently, cystatin C testing is only used in special situations (13).

Staging of chronic kidney disease based on glomerular filtration rate
Table 1
Staging of chronic kidney disease based on glomerular filtration rate
Staging of chronic kidney disease based on albuminuria
Table 2
Staging of chronic kidney disease based on albuminuria

Screening and indication-related examination of renal function

Serum creatinine is not part of the “Check-up 35” examination (14). However, since it is almost always included in the laboratory testing, “de facto” screening can be assumed. The benefit of screening compared to event-triggered testing of renal function with regard to a patient-relevant endpoint has not yet been assessed in prospective studies (15). Given the high number of renal function tests performed in the context of event-triggered diagnostic testing, the low incidence of high-grade renal impairment and the fact that the screening result is of little therapeutic consequence, it appears unlikely that a benefit would be found. For these reasons, the guideline only recommends an indication-related examination in patient populations without CKD, but with an increased risk for CKD (B):

  • Diabetes mellitus once a year (B) (16)
  • Newly diagnosed hypertension (A)
  • Prolonged use of nephrotoxic medications/chemotherapy once a year (B)
  • Positive family history of inherited kidney disease (GCP)
  • Planned use of contrast medium (A).

In case of a temporary treatment with nephrotoxic medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), the need for determining the GFR before and after the treatment should be decided on a case-by-case basis (A). In addition, serum creatinine testing may be indicated in patients with urological disorders, heart failure and other conditions.

It is almost impossible to establish scientifically founded monitoring frequencies; these have to be estimated on a case-by-case basis. Higher frequencies of monitoring may be required in patients with more advanced stages of CKD (Figure).

Recommendations for monitoring frequency (number of monitoring examinations per year)
Figure
Recommendations for monitoring frequency (number of monitoring examinations per year)

Procedure at first diagnosis

In patients with suspected acute renal failure, a follow-up check should be performed not later than two weeks after the initial examination, unless the initial signs and symptoms (edema, dyspnea) necessitate immediate referral or hospital admission (A).

Urine testing

At the time of the first diagnosis of CKD, albuminuria should be quantified as it is an important prognostic marker (A). In a spot urine sample, creatinine and albumin are measured and expressed as albumin-creatinine ratio (ACR) in mg/g (A).

Hematuria may indicate the presence of nephrological or urological problems, such as glomerulonephritis, vasculitis, nephrolithiasis or malignancies. Gross hematuria must always be fully investigated and is not part of the guideline. The prevalence of non-visible hematuria is between 2.5% and 20%, depending on the studied population (17). In patients with newly diagnosed CKD, hematuria should be investigated using a urine reagent strip (A). A positive strip test result should be double-checked by a second independent urine strip test (18).

Clinical diagnosis

Since untreated hypertension is an important risk factors for the progression of CKD, blood pressure should be checked (A). In addition, ultrasonography of the kidneys should be recommended if additional clinical signs and symptoms (Box) are present (A).

Clinical indications for ultrasonography in newly diagnosed chronic kidney disease
Box
Clinical indications for ultrasonography in newly diagnosed chronic kidney disease

Determining the cardiovascular risk

CKD is associated with an increased cardiovascular risk (19). CKD has a hazard ratio of 1.4 for cardiovascular disease, myocardial infarction and heart failure (18). A validated risk calculation instrument should be used to determine the risk (B), such as “arriba”, PROCAM score or ESC score (20, 21). None of these instruments takes renal function into account because including renal function does not improve the predictive power of the instrument.

Management

Non-drug interventions

Being diagnosed with chronic kidney disease can provoke feelings of insecurity and anxiousness. In general, patients should be informed about the diagnosis (A). In the discussion, the typically slow course of primarily age-related renal impairment, which rarely leads to end-stage renal disease, can be highlighted. On the other hand, the approach to medication use (pain killers) or the prevention of dehydration is also addressed (22, 23, 24). When informing the patient, an individual approach is helpful. Supplementary to the guideline, a patient version was created.

Advice on health-related behavior (exercise, nutrition, smoking cessation) should be offered (GCP).

It is necessary to review whether due to the current medications taken by the patient or the prescription of new drugs, a dose adjustment is required or whether there are contraindications (A). Nephrotoxic medications should ideally be avoided. Approximately 50% of medications are eliminated by renal excretion (25). For information about dose adjustment in patients with impaired renal function visit www.dosing.de.

The evidence in support of specific dietary recommendations for patients with early stages of CKD is scarce (26). The recommendations for a healthy diet are largely the same as those for the general population. Starting from CKD G3, the daily consumption of sodium chloride (table salt) in food should not exceed 6 g (approx. 2–3g sodium/day), according to the recommendations of the German Nutrition Society (DGE, Deutsche Gesellschaft für Ernährung). This is lower than the average 9 g to 12 g of table salt consumed daily in Germany. Dietary counselling, addressing potassium, phosphate, sodium chloride and calorie intake, should be adapted to the severity of CKD and started at CKD G4 or higher (B).

The previously recommended dietary protein restriction is not supported by evidence and associated with an increased risk of malnutrition. The recommendations for CKD patients do not differ from the recommendation for adults of a protein intake of 0.8–1.0 g/kg/day issued by the German Nutrition Society (DGE; B) (27, 10).

Clinically relevant disorders of the potassium and phosphate metabolism are rare and expected only from stage 4 CKD onwards. Medications with an effect on the potassium metabolism, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (“sartans”), NSAIDs, or potassium-sparing diuretics, should be used with caution. The reduced ability to excrete sodium observed in patients with CKD can lead to sodium chloride retention and increased blood pressure. Furthermore, a high dietary intake of sodium chloride is associated with proteinuria and glomerular hyperfiltration and can reduce the effectiveness of the pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS), e.g. by ACE inhibitors or sartans.

Pharmacotherapy

For selected kidney diseases, a specific treatment can be offered. The focus of pharmacotherapy is on treating the underlying diseases or co-morbidities and complications that determine the prognosis (12).

Co-morbidities

In patients with blood pressure readings >140/90 mm Hg, corresponding to the hypertension target blood pressure, antihypertensive treatment should be offered (B). The target value should be set on a case-by-case basis (B). Type 2 diabetes should be preferably treated with metformin up to a GFR of 30 mL/min, if HbA1c is not within the individualized target range (B). There is insufficient evidence available on the treatment of hyperuricemia to delay the progression of CKD (statement).

Anemia

The prevalence of anemia increases with increasing impairment of kidney function. Also among patients with CKD, iron deficiency anemia is the most common type of anemia. The development of renal anemia is a multifactorial process. Besides a deficiency in the growth factor erythropoietin, especially from stage G4 onwards, a disorder of iron metabolism also plays a role. The decisions to start treatment is not solely guided by laboratory findings, but is also a clinical one based on symptoms, patient health goals and relevant comorbidities. Since iron absorption in patients with CKD is impaired, mostly in the higher CKD stages, intravenous iron replacement should be considered in patients who failed to respond to oral iron replacement therapy (B). In patients considered kidney transplant candidates, transfusion of cellular blood products should ideally be avoided (B). Patients with clinical symptoms may be offered a referral for a specialist‘s assessment of the indication for the use of erythropoiesis-stimulating agents (ESAs).

Chronic Kidney Disease-Mineral and Bone Disorder

Chronic kidney disease-mineral and bone disorder (CKD-MBD; previously known as renal osteodystrophy) is associated with disturbances of calcium-phosphate metabolism and bone formation as well as extraosseous calcifications, primarily of the blood vessels. Although electrolyte abnormalities rarely occur in patients with early stages of CKD, a steep increase in the prevalence of CKD-MBD is noted in the stages G4 to G5. If this constellation is suspected, the patient should be offered a nephrologist referral (B). Vitamin-D replacement should not be initiated on a routine basis (A). In case of vitamin D deficiency, a consultation and, if indicated, cholecalciferol treatment should be offered (B).

Management of common comorbidities

For the management of cardiovascular risks and treatment with antiplatelet agents and statins, the same recommendations apply as for patients without CKD (A).

The use of NSAIDs for pain relief should ideally be avoided or these agents should be given over the shortest period of time in the lowest dose. Starting from stage G4, they are formally contraindicated in CKD patients (B). Alternative agents are paracetamol and metamizole. If possible, non-pharmacological pain management options should be considered. Any treatment with opioids should be started at a low dose, then gradually increased and carefully adapted based on its clinical effect, potentially also by extending the dosing interval. In patients with CKD G5 (GFR < 15 mL/min), preference should be given to buprenorphine, fentanyl or hydromorphone (25, 28).

In case of severe intercurrent disease with risk of acute-on-chronic renal failure, all potentially nephrotoxic drugs or drugs eliminated by renal excretion should be evaluated, especially NSAIDs, metformin, lithium, digoxin, diuretics, and RAAS inhibitors (ACE inhibitors, sartans, aldosterone inhibitors, direct renin inhibitors) (A). RAAS inhibitors should not be combined with each other or with potassium-sparing diuretics or NSAIDs.

Nephrologist referral or other specialist referrals and interface definition

In a qualitative study among nephrologists, the desired number of nephrologist follow-up appointments was equated to the recommended frequency of laboratory monitoring (29). Especially in elderly CKD patients, this approach is not recommended. It is recommended that in patients with low risk of progression and low risk of end-stage kidney disease, renal function monitoring is carried out by their general practitioners (GPs)/family physicians.

As a rule, interface definitions cannot be established on a scientific basis alone, but are the result of a consensus process (11). In addition, epidemiological considerations and the available health care resources must be taken into account. A distinction should be made between a one-time visit to a nephrologist and the continuous involvement of a nephrologist in the care for these patients (co-provision of care). As a rule, however, all CKD patients with an increased risk of progression to dialysis should be evaluated by a nephrologist to identify potentially treatable causes of impaired renal function, such as primary glomerulonephritis or kidney involvement in patients with systemic autoimmune disease, or to prepare for dialysis or kidney transplant. The decision about nephrological co-provision of care should be made on a case-by-case basis (A). It should be founded on the following factors:

  • Therapeutic consequence
  • Preparation for renal replacement therapy or kidney transplant
  • Indication for special drug therapy, e.g. immunosuppressants, erythropoietin
  • Type and severity of kidney disease
  • Complications, such as CKD-MBD or renal anemia, requiring treatment
  • Patient preferences
  • Co-morbidities
  • Life expectancy.

In very old CKD patients and in the palliative care situation, a personalized decision should be made in consultation with the patient or family members, while in younger patients—arbitrarily set at age <50 years—a liberal referral decision should be made (B).

Nephrologist referral is recommended when the following criteria apply:

  • Newly detected GFR <30 mL/min for consultative examination (B)
  • GFR 30–59 mL/min and one of the following factors (B): hematuria not explained by a urological condition, albuminuria category ≥ A2 or refractory hypertension with three or more antihypertensive agents
  • Rapid progression (B)

In case of signs of obstructive uropathy, urologist referral should be offered (B).

Persons with close relatives with hereditary kidney disease, for example autosomal dominant polycystic kidney disease (ADPKD), should be informed about the option of nephrological or genetic counselling (B).

Monitoring

In patients diagnosed with chronic kidney disease, renal function should be monitored at regular intervals with the aim to detect relevant disease progression and to be able to prevent or adequately treat complications. The frequency of monitoring should be arranged with the patient on a case-by-case basis (A). As a guidance, there is a proposal of recommendations which are adapted to the CKD stage (Figure) (B). During these follow-up examinations, the patient’s blood pressure should be checked (B). ACR-based testing for urinary protein excretion is only recommended if proteinuria was initially detected or on a case-by-case basis in patients with diabetes. Monitoring is not recommended in patients without diabetes in whom proteinuria was initially ruled out (B). From stage G3 onwards, a drug review of the long-term medication should be carried out at least once a year (A). The monitoring examinations are summarized in the eMethods section (Table 3).

Overview of monitoring criteria in patients with known chronic kidney disease
Table 3
Overview of monitoring criteria in patients with known chronic kidney disease

Need for research

The following research questions arose from the review of the available literature and guidelines:

  • What type of care is provided to dialysis patients in primary care?
  • What GFR and ACR monitoring intervals are sufficient in CKD patients to prevent complications?
  • How can the prognosis of CKD and its complications be objectively assessed in older patients to allow adequate adaption of patient information, treatment intensity and monitoring?

Clinical guidelines are not peer-reviewed in the Deutsches Ärzteblatt, as well as in many other journals, because clinical (S3) guidelines are texts which have already been repeatedly evaluated, discussed and broadly consented by experts (peers).

Financial support

The guideline was made possible by support of the KfH Foundation Preventive Medicine (KfH-Stiftung Präventivmedizin) and the Damp Foundation (Damp-Stiftung). The foundations had no influence on the content of the research.

Acknowledgement

We would like to take this opportunity to thank all those who were involved in the development of the guideline and made this guideline possible.

Conflict of interest statement

Conflicts of interest were identified using the AWMF ‘s structured questionnaires so that they could be taken into account in the guideline process. The authors of the guideline had no conflicts of interest. The results of the investigation were published in the guideline report (30).

The authors declare that no conflict of interest exists.

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Prof. Dr. med. Gesine Weckmann
Abteilung Allgemeinmedizin
Universitätsmedizin Greifswald
Fleischmannstraße 6, 17475 Greifswald, Germany
allgemeinmedizin@uni-greifswald.de

Cite this as:
Weckmann G, Chenot JF, Stracke S: Clinical practice guideline:
The management of non–dialysis-dependent chronic kidney disease in primary care. Dtsch Arztebl Int 2020; 117: 745–51. DOI: 10.3238/arztebl.2020.0745

Supplementary material

For eReferences please refer to:
www.aerzteblatt-international.de/ref4420

eMethods, eTables, eFigure, eBox:
www.aerzteblatt-international.de/20m0745

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Brück K, Stel VS, Gambaro G, et al.: CKD prevalence varies across the European general population. J Am Soc Nephrol 2016; 27: 2135–47 CrossRef MEDLINE PubMed Central
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Stel VS, Brück K, Fraser S, et al.: International differences in chronic kidney disease prevalence: a key public health and epidemiologic research issue. Nephrol Dial Transplant 2017; 32 (Suppl 2): ii129–35 CrossRef MEDLINE
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Hill NR, Fatoba ST, Oke JL, et al.: Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS One 2016; 11: e0158765 CrossRef MEDLINE PubMed Central
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Weckmann G, Stracke S, Chenot J-F: DEGAM S3-Leitlinie Nr. 22 Versorgung von Patienten mit chronischer nicht-dialysepflichtiger Nierenerkrankung in der Hausarztpraxis“. AWMF-Register-Nr. 053–048. Leitlinienreport, 1. Auflage. Version 1. 2019.
Department of General Practice and Family Medicine, University Medicine Greifswald (UMG), Institute of Community Medicine, Greifswald, Germany: Prof. Dr. med. Gesine Weckmann, Prof. Dr. med. Jean-François Chenot, MPH
European University of Applied Sciences (EU|FH) Rhein/Erft, Faculty of Applied Health Sciences, Rostock, Germany: Prof. Dr. med. Gesine Weckmann
Department of Internal Medicine A, Nephrology, University Medicine Greifswald, Greifswald, Germany: Prof. Dr. med. Sylvia Stracke, MME
KfH Kidney Center Greifswald, Greifswald, Germany: Prof. Dr. med. Sylvia Stracke, MME
Clinical indications for ultrasonography in newly diagnosed chronic kidney disease
Box
Clinical indications for ultrasonography in newly diagnosed chronic kidney disease
Recommendations for monitoring frequency (number of monitoring examinations per year)
Figure
Recommendations for monitoring frequency (number of monitoring examinations per year)
Key messages
Staging of chronic kidney disease based on glomerular filtration rate
Table 1
Staging of chronic kidney disease based on glomerular filtration rate
Staging of chronic kidney disease based on albuminuria
Table 2
Staging of chronic kidney disease based on albuminuria
Overview of monitoring criteria in patients with known chronic kidney disease
Table 3
Overview of monitoring criteria in patients with known chronic kidney disease
Contributors to the development of the guideline
eBox
Contributors to the development of the guideline
Flowchart of the results of the systematic search and selection of the literature CKD, chronic kidney disease; HIV, human immunodeficiency virus
eFigure
Flowchart of the results of the systematic search and selection of the literature CKD, chronic kidney disease; HIV, human immunodeficiency virus
Key questions
eTable 1
Key questions
Assessment of the methodological quality of the guideline using the AGREE-II instrument
eTable 2
Assessment of the methodological quality of the guideline using the AGREE-II instrument
1.Levey AS, de Jong PE, Coresh J, et al.: The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2011; 80: 17–28 CrossRef MEDLINE
2.Girndt M, Trocchi P, Scheidt-Nave C, Markau S, Stang A: The prevalence of renal failure. Results from the German Health Interview and Examination Survey for Adults, 2008–2011 (DEGS1). Dtsch Arztebl Int 2016; 113: 85–91 VOLLTEXT
3.Brück K, Stel VS, Gambaro G, et al.: CKD prevalence varies across the European general population. J Am Soc Nephrol 2016; 27: 2135–47 CrossRef MEDLINE PubMed Central
4.Stel VS, Brück K, Fraser S, et al.: International differences in chronic kidney disease prevalence: a key public health and epidemiologic research issue. Nephrol Dial Transplant 2017; 32 (Suppl 2): ii129–35 CrossRef MEDLINE
5.Hill NR, Fatoba ST, Oke JL, et al.: Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS One 2016; 11: e0158765 CrossRef MEDLINE PubMed Central
6.Xie Y, Bowe B, Mokdad AH, et al.: Analysis of the global burden of disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. Kidney Int 2018; 94: 567–81 CrossRef MEDLINE
7.Hoffmann F, Boeschen D, Dörks M, Herget-Rosenthal S, Petersen J, Schmiemann G: Renal insufficiency and medication in nursing home residents—a cross-sectional study (IMREN). Dtsch Arztebl Int 2016; 113: 92–8 VOLLTEXT
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