What to do in case of chronic creatinine increase?

The proportion of patients with CKD increases sharply with age. The most common causes are diabetes mellitus and arterial hypertension. Early onset of secondary complications can significantly affect the prognosis. Determination of eGFR and albumin can detect and prognostically assess CKD in a timely manner.

Chronic kidney disease

An increase in plasma or serum creatinine (P-/S-creatinine) lasting longer than 3 months and an associated reduction in glomerular filtration rate (GFR) is considered indicative of chronic kidney disease (CKD). This usually runs silently over a long period of time and is therefore often diagnosed too late. In most cases, CKD is due to diabestes mellitus or arterial hypertension. Thus, both diseases are risk factors for the development of structural damage to the kidney. Only with increasing severity of renal damage does renal function become impaired, leading to a decrease in GFR or an increase in creatinine. Thus, the chronic increase in creatinine does not mark the onset of kidney disease, but is an expression of kidney damage that has already developed over a longer period of time (Fig. 1). This can be detected at an early stage with the aid of the albumin/creatinine ratio in spontaneous urine. Thus, only the combined observation of GFR as a marker of renal function and albumin/creatinine ratio as a marker of renal damage allows the diagnosis of CKD and its prognostic assessment (Table 1).

A multicenter cross-sectional study found that in Swiss primary care practices, about 10% of patients had reduced GFR (<60 mL/min/1.73^m2) and about 17% had relevant albuminuria (≥30 mg/g creatinine). This proportion increased sharply with age and was 34% and 33%, respectively, in the group over 75 years of age. Overall, about ¼ of the study participants examined had CKD. A study from Germany showed that only less than 30% of those affected were aware of their kidney dysfunction and only two-thirds of those who were aware were receiving medical treatment. These figures are worrying in that even mild impairment of kidney function develops secondary complications that lead to a sharp increase in cardiovascular disease, which in turn is associated with a significant reduction in life expectancy (Fig. 1). For this reason, kidney disease and its secondary complications must be diagnosed and treated at an early stage in order to favorably influence the course of kidney disease and reduce mortality.

Assessment of kidney function

Creatinine: Creatinine, a breakdown product of muscle metabolism, has long been established in practice as an endogenous marker of GFR. However, its P-/S concentration is affected by numerous influencing factors, so that it is not an ideal marker of GFR a priori (Tab. 2) . Among the most important influencing factors is muscle mass, which in turn is determined by age, gender and ethnic origin. Furthermore, dietary habits and nutritional status as well as liver function (production of the precursor creatine) affect P-/S-creatinine. After its release from the muscles into the circulation, creatinine is freely filtered glomerularly due to its low molecular weight (113 Da), but in addition it is also secreted tubularly and excreted to a small extent via the intestine. Tubular secretion becomes particularly important in the presence of preexisting renal dysfunction. In this situation, administration of drugs that inhibit tubular secretion can cause a sharp increase in P-/S-creatinine that is independent of GFR, leading to misjudgments of renal function.

Due to the influencing factors, creatinine shows only a very poor correlation with GFR. With a P-/S-creatinine of 1.0 mg/dL (88 mol/L), GFR can range from 20 to 120 mL/min per 1.73^m2. In addition, P-/S-creatinine does not increase significantly until the GFR drops to <60 mL/min/1.73^m2 (“creatinine-blind range”). At this point, more than half of all nephrons are already non-functional. Therefore, creatinine is not a priori suitable as an early marker of renal disease. Thus, even with a P-/S-creatinine or GFR in the normal range, renal disease cannot be ruled out.

In addition, the method of measurement must be considered. While most laboratories now use a reliable enzymatic method to determine creatinine, the Jaffé method (nonspecific color reaction) is still occasionally used for cost reasons. This method can be strongly influenced by numerous “pseudocreatinins” circulating in the blood. These include bilirubin, ketones, glucose, protein, ascorbic acid and drugs (antibiotics).

Cystatin C: Cystatin C is a plasma protein produced by all nucleated cells in the body and released into the blood at a constant rate. Due to its low molecular weight (13 kDa), it is freely filtered glomerularly and subsequently reabsorbed and metabolized in the proximal tubule. Unlike creatinine, it is not secreted tubularly. Cystatin C is also less influenced by liver function and musculature and thus hardly affected by age, gender and diet (Table 2) . This results in the following advantages of cystatin C over creatinine:

• higher diagnostic sensitivity, thus earlier detection of GFR impairment in the diagnostically relevant range of 30 to 90 mL/min/1.73^m2
• more reliable in case of strongly deviating muscle mass and liver cirrhosis
• faster detection of acute renal dysfunction
• Also suitable for the assessment of GFR in children from the age of 2 years without sex-dependent reference values

It should be noted that especially inflammatory processes, hyperthyroidism and hypothyroidism as well as high-dose steroid administration can lead to a GFR-independent change in P-/S-cystatin.

Overall, cystatin C is clearly superior to creatinine as an endogenous marker of GFR. However, due to the higher costs, it plays only a minor role in daily practice.

Calculation algorithms for estimating GFR (eGFR): Today, it is recommended to avoid reporting P-/S-creatinine or P-/S-cystatin C alone on laboratory findings. Instead, GFR should be estimated using calculation algorithms and reported as eGFR (e for estimated). When calculating eGFR, most calculation algorithms primarily consider the influence of age, gender, and ethnicity. A number of different calculation formulas are now available for creatinine and cystatin C, as well as the combined calculation of creatinine and cystatin C (Table 3). The latter is said to have a higher overall accuracy. In principle, however, the following aspects must be taken into account when using the calculation algorithms:

• They have been evaluated in different populations with different age structures and therefore should only be used in the age groups studied.
• They require stable renal function and are therefore not suitable for acute changes in renal function.
• Even with their help, only limited accuracy (approx. ±30%) can be achieved.

Currently, the use of the CKD-EPI formula is recommended because it has been most extensively evaluated. It should be noted that the CKD-EPI formula, however, is not suitable for children and adolescents and elderly patients. Other calculation formulas are now available for these age groups (Schwartz formula for ages 1-16 years, BIS formula for ages ≥70years, and FAS formula for ages 2-100 years) (Table 3).

Laboratory diagnosis of structural renal damage

Since structural damage to the kidney manifests itself before the actual renal dysfunction, the laboratory diagnostic detection of this damage is of particular importance in terms of early detection. Urinalysis is at the center of this diagnostic procedure. Here, the following three examinations are carried out:

• Urine test strips
• Microscopic examination of the urine sediment
• Proteinuria Diagnostics

Urine test strips: Urine test strips allow semi-quantitative screening for:

• Microhematuria (test field: blood/hemoglobin)
• Proteinuria (test field: protein)

A particular strength of urine test strips is the detection of bleeding. Since they have a very low detection limit for erythrocytes (5 erythrocytes/μL), they can detect even the slightest bleeding not visible to the naked eye in urine (microhematuria). However, they are unable to distinguish between hemorrhage and hemolysis (in both cases there is release of hemoglobin) and rhabdomyolysis (release of myoglobin) due to the underlying peroxidase reaction. Therefore, a microscopic examination of the urine sediment must subsequently be performed for further differentiation.

Urine test strips are only suitable to a limited extent for the detection of proteinuria. The corresponding test field reacts primarily to the negatively charged albumin. Other proteins such as immunoglobulins, light chains, tubular marker proteins, etc. are not included. In addition, the detection limit of normal urine test strips is approximately 100 to 300 mg/L, so that microalbuminuria, as occurs in the early stages of diabetic nephropathy, cannot be detected at an early stage. Although commercially available special test strips are available for this purpose. Nevertheless, for accurate detection of proteinuria and its further differentiation, quantitative proteinuria diagnostics should be performed in the laboratory, since only with these methods can the influence of urine excretion and concentration on the protein concentration in urine also be taken into account by relating protein to creatinine excretion (protein/creatinine ratio).

Urine sediment: Urine sediment can provide important clues to the localization of the source of bleeding in the presence of microhematuria. Thus, erythrocyte cylinders indicate an “intrarenal” source of bleeding. The matrix of these cylinders consists of uromodulin (Tamm-Horsfall protein), a protein produced by epithelial cells of the renal tubules and released into the tubule lumen. There, uromodulin encloses all corpuscular elements, leading to the formation of cylinders.

The next step is to differentiate glomerular from tubulointerstitial damage. For this purpose, acanthocytes are searched for. These are erythrocytes with typical cone-shaped protuberances (“Mickey Mouse ears”). These occur when erythrocytes pass through a severely damaged glomerular basement membrane. A proportion of more than 5% acanthocytes in the urine is considered an important diagnostic indicator for glomerulonephritis or basement membrane disease.

In summary, microhematuria can be differentiated as follows:

• Suspected urinary tract disease: hematuria , no erythrocyte cylinders, no acanthocytes.
• Suspected tubulointerstitial kidney disease (e.g., drug-induced or infectious): Hematuria with erythrocyte cylinder, no acanthocytes.
• Suspicion of glomerular kidney disease (glomerulonephritis, basement membrane disease): Hematuria with erythrocyte cylinder and acanthocytes (>5%) – (“Active Sediment”).

Quantitative proteinuria diagnostics: Hereby, structural damage of the glomerular basement membrane can be detected early, quantified and differentiated from tubular damage. For this purpose, marker proteins are analyzed in spontaneous urine, preferably second morning urine, and reported as protein/creatinine ratio. The reference to creatinine, which is constantly excreted in the urine in proportion to muscle mass, serves to correct for variations in urine volume and concentration.

However, a valid result requires attention to the following limitations that may affect either urinary creatinine and/or protein excretion:

• Abnormal muscle mass
• No steady state
• High protein intake
• Strong physical effort
• Urinary tract infection
• Hyperfiltration
• Menstruation

Special attention should be paid to the presence of hyperfiltration (increased GFR, e.g. pregnancy, early stage of diabetes mellitus), as this reduces the sensitivity of urine analysis (urine strip tests and proteinuria diagnostics). In the presence of limitations, protein excretion should be determined exceptionally in 24-hour collection urine. Otherwise, 24-hour urine collection should not be performed to determine marker proteins because the method is laborious and prone to error. Suitable marker proteins are:

• Albumin: marker of glomerular anion filtering function.
• Immunoglobulin G (IgG): Marker of glomerular molecular sieve function.
• α _{1-microglobulin}: tubular damage marker.

By determining albumin and IgG together, glomerular damage can be detected early and differentiated with regard to its extent. Depending on the degree of damage, a distinction is made:

• Microalbuminuria (albumin excretion 30-300 mg/g creatinine).
• Selective glomerular proteinuria (albumin excretion >300 mg/g creatinine)
• Unselective-glomerular proteinuria (albumin + IgG excretion increased).

Additional determination of α1-microglobulin, which is freely filtered glomerularly and reabsorbed tubularly, can also detect tubulointerstitial diseases.

Rationale for chronic creatinine elevation: If there is a chronic creatinine elevation, there is an urgent suspicion of CKD. The first step is to confirm these diagnostically and to quantify their extent (table 1) . In addition, initial etiological clarification should be sought (Tab. 4).

Diagnostics of CKD

1. detection of functional renal impairment: initially, P-/S-creatinine should be determined by an enzymatic method and eGFRcreatinine should be calculated by CKD-EPI formula . Age-appropriate formulas should be used for younger and older patients (Table 3). The performance of a 24-hour creatinine clearance is now only recommended in exceptional cases (limitations of creatinine and/or protein excretion) due to the high susceptibility to error.

If the eGFR <is 60 mL/min/1.73m2, then renal dysfunction is suspected. Before confirming the diagnosis, the following limitations of eGFRcreatinine must be considered:

• eGFR in the range of 45-59 mL/min/1.73m2
• Acute changes in renal function (not steady state).
• Influencing factors:
  • Age <18 years, very old age
  • Very much (bodybuilding) or little muscle mass (cachexia)
  • Muscle diseases or paralysis
  • Strongly deviating body mass (obesity, amputation)
  • Severe diseases (e.g. tumor)
  • Cirrhosis of the liver
  • Protein or creatine supplementation
  • High meat consumption or vegetarian
  • Drugs that inhibit tubular creatinine secretion.

If limitations are present, confirmatory diagnostics using P-/S-Cystatin C and calculation of eGFRCystatin is recommended. Alternatively, a combined eGFRcreatinine-cystatin_C can be calculated. In special situations (e.g., dose determination during cytostatic therapy), a clearance investigation with an exogenous marker should be performed at least initially to determine a precise mGFR. It also helps to estimate the deviation of eGFR from mGFR in an individual case.

Chronic renal dysfunction is considered confirmed when eGFRCystatin, eGFRcreatinine-cystatin_C, or mGFR results in a value of <60 mL/min/1.73^m2 on at least two determinations over the course of 3 months. With the help of the KDIGO guideline, renal function impairment can then be additionally classified into different stages (G1-5) (Table 1).

It should be noted that in the current KDIGO guideline, stage 3 has been further subdivided into stages 3a and 3b, as patients in stage 3b have a significantly higher risk of terminal renal failure and the occurrence of cardiovascular complications.

Another challenge in daily practice is the assessment of physiological variations in GFR. According to KDIGO, progression of renal impairment can be assumed when GFR decreases by ≥25%. Overall, the accuracy of the assessment increases with the number of GFR determinations and the length of the observation period.

2. detection of structural kidney damage: Initial evidence of structural renal damage is provided by determination of the albumin/creatinine ratio (ACR) in spontaneous urine. To detect albu-min-uria, three examinations should be performed, each one week apart. If more than 2 analyses are positive, then albuminuria is considered confirmed. According to the extent of albuminuria, a staging into three severity levels (A1-A3) can be performed (Tab. 1).

3. assessment of prognosis: with the help of the risk-dia-gram-mes (KDIGO-heatmap), a prognostic assessment of CKD can be made by looking at GFR and albuminuria together (tab. 1) . This can also be used as a basis for the intervals of monitoring eGFR and ACR in patients. The risk diagram highlights the particular importance of albuminuria, as even with a GFR of ≥90 mL/min/1.73m2, albuminuria significantly worsens the prognosis of CKD (Table 1).

Initial etiological clarification

Initial indications of the etiology of CKD are obtained with the aid of urine analysis. At intervals of one week each, 3 examinations should be performed using urine test strips to detect microhematuria. If at least two findings are positive, then microhematuria is considered confirmed. In this case, a targeted search for erythrocytes and acanthocytes should be performed in the urine sediment to achieve an initial differentiation of the bleeding source (Table 4).

In the presence of albuminuria, further differentiation of proteinuria should be performed by additional determination of IgG and α1-microglobulinwith the aim of assessing the potential extent of glomerular damage and detecting tubular damage (Table 4).

In addition, ultrasonography of the kidneys and urinary tract should be considered for a GFR <60 mL/min/1.73^m2 if the following factors are present:

• Progression of CKD
• GFR <30 mL/min/1.73^m2
• Macro- or persistent microhematuria
• Significant proteinuria
• Suspicion of obstructive uropathy
• Family history of polycystic kidney disease
• V.a. Tumor

Furthermore, the detection of shrunken kidneys allows an additional prognostic assessment and size differences of the kidneys can give a first indication for the presence of renal artery stenosis (Table 4).

Diagnostics of CKD secondary complications

In the course of CKD, characteristic secondary complications develop even with mild GFR impairment. These include renal anemia and secondary hyperparathyroidism. The detection of both substantiates the suspicion of a chronic disease process in the sense of CKD. In later stages of CKD, disturbances of the acid-base (e.g. metabolic acidosis) and electrolyte (e.g. hyperkalemia) balance can also be detected (Table 4).

1. renal anemia: renal anemia may develop even with mildly impaired GFR. The main cause is decreased formation of erythropoietin in the kidneys. This results in delayed maturation of erythrocytes in the bone marrow. The blood count usually shows normochromic, normocytic anemia. If there is no anemia, no further laboratory tests are initially necessary. In contrast, if anemia is present, other laboratory values must be specifically analyzed, since renal anemia is a diagnosis of exclusion.

2. secondary hyperparathyroidism: Laboratory chemical changes indicative of secondary hyperparathyroidism (sHPT) occur in early stages of CKD. Conditional on early renal retention of phosphate, a cascade of metabolic-endocrine changes is triggered that manifest in the laboratory as follows:

• Fibroblast growth factor 23 (FGF 23) ↑
• Parathyroid hormone ↑
• Phosphate ↑
• 1,25(OH)2 vitamin D ↓
• Calcium ↑

These laboratory changes are not only the basis for the diagnosis of sHPT, but also serve for monitoring during the course of therapy.

Referral of patients and patients

Due to the increasing number of patients with age, a differentiated referral strategy is necessary for patients with CKD. The DEGAM S3 guideline suggests the following indications:

Referral to a nephrologist: In early stages of renal failure, the patient should be evaluated by a renal specialist on a consultative basis if there is any uncertainty in order to identify underlying and treatable renal disease early and to adequately treat early complications. A referral should be made in the following cases:

• GFR <30-45 mL/min/1.73^m2 (G3b)
• Initial diagnosis of CKD with
  • persistent hematuria that cannot be explained by urology
  • Albuminuria stage ≥A2
  • Refractory hypertension with ≥3antihypertensive medications.
  • rapid progression
• In <50-year-olds, the referral indication should be generous
• For >70-year-olds, comorbidities and individual health goals should be considered

Referral to urologist

• Indication of obstructive uropathy
• Macrohematuria
• Persistent microhematuria without erythrocyte cylinders and acanthocytes.

Monitoring

In the recommendations on monitoring, the S3 guideline of DEGAM suggests individual monitoring intervals for eGFRcreatinine depending on the stage of CKD (Table 1). In patients with proven proteinuria, ACR should also be monitored at these intervals. Individual ACR control intervals, on the other hand, should be agreed upon for diabetes mellitus.

Take-Home Messages

• In primary care practice, the proportion of patients with CKD increases sharply with age. The most common causes are diabetes mellitus and arterial hypertension.
• The prognosis of patients with CKD is mainly affected by early-onset secondary complications (arterial hypertension, renal anemia, secondary hyperparathyroidism) and associated cardiovascular disease.
• Creatinine is not an ideal marker for assessing GFR due to numerous influencing factors. Cystatin C is superior to creatinine.
• Joint determination of eGFR (marker of renal dysfunction) and albumin/creatinine ratio in spontaneous urine (marker of renal impairment) allows early detection and prognostic assessment of CKD (KDIGO heat map).
• Initial etiologic workup of CKD can be performed quickly and easily using urine test strips (microhematuria, proteinuria), urine sediment (erythrocyte cylinders, acanthocytes), and quantitative proteinuria diagnostics (glomerular/tubular proteinuria) and ultrasonography.

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CARDIOVASC 2021; 20(4): 12-18