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Chronic kidney disease in patients with recurrent nephrolithiasis and concomitant damage to the cardiovascular system

https://doi.org/10.21886/2308-6424-2021-9-3-52-61

Abstract

Introduction. Chronic kidney disease (CKD) is commonly diagnosed in patients with cardiovascular diseases (CVDs) and also manifests itself in most patients with urolithiasis. Numerous studies have shown that renal dysfunction is not only directly related to the high risk of developing various CVDs and chronic heart failure (CHF) as one of the most common complications but also the mortality rate in comorbid patients. CKD and CHF have similar pathogenetic mechanisms and common target organs; co-existing, both pathological conditions accelerate the progression of major diseases and significantly aggravate their course. In patients with recurrent nephrolithiasis combined with CVDs, all the causes leading to the formation of CKD (recurrent obstructive pyelonephritis, nephroangiosclerosis, etc.) are present to some extent.

Purpose of the study. To evaluate the incidence and characteristics of CKD in patients suffering from recurrent urolithiasis associated with CVDs.

Materials and methods. The prospective study included 406 patients who were treated for recurrent nephrolithiasis and concomitant CVDs from 2007 to 2020 (Urology Division, Burdenko Principal Military Clinical Hospital). From long-term follow-up respondents who lived at least 10 years after inclusion in the study (n = 52), three groups were formed: group I (n = 18) included patients with a combination of essential hypertension (EH) and ischemic heart disease (IHD), complicated by CHF; group II (n = 15) consisted of patients with uncomplicated CVDs (EH – 7 patients, IHD – 8 patients). The control group III (n = 19) included respondents suffering from nephrolithiasis without CVDs. The glomerular filtration rate (GFR) was determined by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) following the Russian National Guidelines for «Chronic Kidney Disease». The analysis of the obtained data was carried out using Statistica 8.0; the Fisher and Wilcoxon criteria were calculated; the differences were considered significant at p < 0.05.

Results. All patients included in the study were repeatedly hospitalized urgently and as planned and underwent at least one non-invasive manipulation or surgery. The average age of the patients was 58.9 ± 2.95 years; men predominated (~ 75 – 78%). A GFR decrease was recorded in 41.1% of patients included in the study, in 40.5% of patients with a combination of nephrolithiasis and uncomplicated CVDs, Also, its decrease was found in 60 (58.8%) of patients with chronic heart failure (CHF) in 41.1% of cases from the general sample and 40.5% of patients without CHF. CKD stage II occurred in 44 (43.1%) cases of CHF; CKD stages III Ca and Cb were detected in 10 (9.8%) and 4 (1%) cases, respectively; CKD stage IV developed in 1 (0.25%) patient with one of the re-hospitalizations. Of the 52 patients included in the second study part, the ratio of men and women was 41/11 (78.8 and 21.2%, respectively). All three groups were also dominated by men. The initial values of GFR in group I patients significantly differed from those in the control group; in group II, statistically significant differences appeared 4 years after the s the study initiation, and in group I – after 2 years. A sharp (1.5-fold) significant decrease in renal filtration function was registered in group I by the 6th research year, in group II (1.3-fold) – by the 8th research year, and in group III (1.28-fold) – only by the 10th research year. The GFR level in group I and group II decreased during the 1st follow-up year by 2.36 and 1.65 times, respectively.

Conclusion. CKD in patients suffering from recurrent nephrolithiasis in combination with IHD and EH is generally benign. The progression rate of filtration deficiency is relatively low and is (at least in the early stages) about 4.5 ml/min per year. The addition of CHF increases the rate of decline in renal filtration function by up to 25% (from 4 ml/min per year to 5 ml/min per year). The main negative effect of concomitant CVDs (especially complicated CHF) is not an ultrahigh decrease in GFR but a reduction in kidney functioning stable period up to complete cessation.

For citation:


Royuk R.V., Yarovoy S.K. Chronic kidney disease in patients with recurrent nephrolithiasis and concomitant damage to the cardiovascular system. Vestnik Urologii. 2021;9(3):52-61. (In Russ.) https://doi.org/10.21886/2308-6424-2021-9-3-52-61

Introduction

Presently, the term “Chronic Kidney Disease” (CKD) proposed in 2020 by the National Kidney Foundation (NKF, USA) and Kidney Disease Outcomes Quality Initiative (КDOQI, USA), has replaced the term “Chronic Renal Insufficiency” in the International Disease Classification (10th revision) and clinical practice [1].

As a rule, CKD is diagnosed in patients with the hypertonic disease, diabetes, cardiovascular diseases (CVDs), and nephrolithiasis [2][3][4][5][6]. The meta-analysis of numerous studies performed by Matsushita еt al. (2010) demonstrated that impairments of renal function in patients with CKD were directly associated with a high risk of development of different CVDs (atherosclerosis, hypertonic disease, ischemic heart disease, etc) [7]. One of the most frequent complications in patients with CKD was chronic heart failure (CHF) [6][7][8][9][10].

Both pathological conditions (CKD and CHF) have similar pathogenetic mechanisms and mutual target organs that co-exist and accelerate the progression of the primary disease and aggravate their development. As a result, comorbid patients get hospitalized more frequently, require intensive or replacement therapy, and surgical interventions. Besides, they have an increased risk of lethal outcomes [11][12][13]. The study conducted by Löfman et al. (2016) demonstrated a direct correlation between a decrease in renal function and the level of lethality in patients with nephrolithiasis and CHF [14].

More and more doctors of different specialities observe comorbid nephrolithiasis and CVDs in patients. Lately, the share of such patients is increasing. According to our data, it increased by 1.9 times within the past decade and became 31.7% [15]. Ischemic heart disease (IHD) complicated with CKD is registered in 20.9% of patients with nephrolithiasis and CHF of various degrees is observed in 25.3% of cases in combination with IHD and recurrent nephrolithiasis [15].

In patients with recurrent nephrolithiasis and chronic CVDs, there are several simultaneous reasons (in the descending order of significance) for renal function impairment/development of CKD [9]: recurrent obstructive pyelonephritis, nephroangiosclerosis, obstructive nephropathy [16], chronic tubulointerstitial nephritis, iatrogenic, or posttraumatic renal tissue damage (repeated contusions during distant lithotripsy, numerous mechanical injuries during open and percutaneous interventions) [17][18][19].

From the author’s point of view, the main one is recurrent pyelonephritis, which attacks quickly lead to the formation of nephrosclerosis [20, 21]. The previous study conducted by the authors showed that in 59.4% of patients, stones were localized in kidneys and repeated recurrence of chronic obstructive pyelonephritis occurred 1.5 times more often. It can be explained by the maintenance of the inflammatory process in kidneys in patients with existing or progressing nephrosclerosis and by an increased tendency for stones formation [15].

The second significant reason is primarily observed in patients of therapeutic, cardiologic, and pulmonologic profiles. Nephroangiosclerosis is a bilateral (in patients with systemic arterial hypertension) nephropathy that develops when small renal arteries and arterioles get affected [22]. Before the development of severe renal insufficiency, nephroangiosclerosis does not have clinical manifestations and gets revealed during the examination of a patient [20][22].

Urinary tract obstruction (without infectious component) leads to a reversible reduction of filtration function of the affected kidney, and then, to irreversible alterations of renal parenchyma and nephrosclerosis.

Chronic tubulointerstitial nephritis (in this context, non-infectious) is a slowly progressing symmetric pathological process that primarily affects renal tubule and interstitial tissue because of urate (gouty) nephropathy [23][24]. Another form of gouty nephropathy, which is more familiar to urologists, is recurrent urate nephrolithiasis. It is more frequently diagnosed in patients with comorbid essential hypertension (EHT) and IHD than in the general population. In patients with expressed metabolic disorders of purines, comorbidity of these forms of nephropathy can be observed [23][24][25].

The study aimed to evaluate the incidence rate and characteristics of CKD in patients suffering from recurrent nephrolithiasis associated with CVDs.

Materials and Methods

A prospective study included 406 patients that were treated for recurrent nephrolithiasis and concomitant CVDs at Urology Division No.1 of Burdenko Main Military Clinical Hospital from 2007 to 2020.

Criteria of the study inclusion:

  • Combination of nephrolithiasis and IHD (any form);
  • Combination of nephrolithiasis and IHD (any stage);
  • Combination of nephrolithiasis, IHD, and EHT.

Criteria of the study exclusion:

  • Age < 18 years old;
  • Symptomatic nephrolithiasis (hyperparathyroidism, tubular dysfunction of any etiology, psoriasis, hemolytic anemia, etc.);
  • Immune deficiency state (decompensated diabetes mellitus, malignant neoplasms of any localization, immune suppressive therapy);
  • Concomitant chronic infectious processes of other localizations at the stage of aggravation;
  • Reduced renal filtration (GFR < 40 ml/min);
  • Hepatic insufficiency;
  • Thyroid disorders (hypothyroidism and hyperthyroidism);
  • Combination of CVDs and any form of diabetes mellitus.

CVDs uncomplicated by CHF was observed in 304 (74.9%) patients (EHT – in 66 cases (21.7%), IHD – in 61 cases (20.1%); IHD + EHT – in 177 cases (58.2%)). In this part of the cohort, a decrease in the GFR was registered in 128 (42.1%) cases. Out of 102 patients with CHF of various severity, there were 60 (58.8%) patients with reduced renal function. Three groups were formed out of patients with a long-term follow-up that survived for more than 10 years from the time of inclusion in the study (n = 52). Group I (n = 18) included patients with a combination of EHT and IHD complicates with CHF. Group II (n = 15) consisted of patients with uncomplicated CVDs (EHT – 7 patients, IHD – 8 patients). Group III (n = 19) was a control group and included respondents that had Kidney Stone Disease without CVDs. The patients were chosen randomly in this part of the study when they were repeatedly admitted to the hospital 2 years (± 2 months) after the previous hospitalization.

The stages of CHF were identified according to the Vasilenko-Strazhesko classification (1935). The stages of EHT were diagnosed according to guidelines of the Society of Cardiology of the Russian Federation (2004). GFR was estimated by the formula CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) according to the national guidelines «Chronic Kidney Disease» [26], [27]. Considering the level of creatinine increase associated with reduced filtration of kidneys in patients with recurrent nephrolithiasis, CVDs, and exacerbation of any of these diseases, it was feasible to use minimal parameters for the estimations during the current hospitalization.

Statistical analysis. The analysis of the obtained data was performed using the methods of descriptive and variation statistics as well as Fisher’s test [Fischer R.] (Bonferroni correction [Bonferroni C.E.]) and Wilcoxon’s test [Wilcoxon F.] in the Statistica 8.0 software (StatSoft Inc., Tusla, CA, USA). The differences were significant at p < 0.05.

Results

All patients included in the study were hospitalized several times in urgent and planned conditions. All patients had at least one non-invasive manipulation or surgical intervention. The mean age of patients was 58.9 ± 2.95 years old (min = 32, Me = 64, max = 83). There were more male patients in the study (~ 75.0 – 78.0%). A decrease in GFR was registered in 41.1% of patients included in the study; in 40.5% of patients with nephrolithiasis combined with uncomplicated CVDs; and in 60 (58.8%) patients with CHF (Table 1).

Table 1. Results of measuring the glomerular filtration rate in patients included in the study (n = 406) and their distribution by stages of chronic kidney disease

CKD stages

Patient groups

Total

n = 406 (%)

CVDs complicated by CHF (n = 102)

CVDs without CHF

n = 304 (%)

I

n = 50 (%)

II А

n = 32 (%)

II B

n = 20 (%)

Total

n = 102 (%)

II (GFR3 = 60 – 89 ml/min)

13 (26.0)1

21 (65.6)

10 (50.0)

44 (43.0)

123 (40.5)

167 (41.1)

III Ca (GFR = 45 – 59 ml/min)

2 (4.0)

3 (9.4)

5 (25.0)

10 (9.8)3

5 (1.6)4

15 (3.7)

III Cв (GFR = 30 – 44 ml/min)

1 (2.0)

2 (6.2)

1 (5.0)

4 (3.9)

0

4 (1.0)

IV (GFR = 45 – 59 ml/min)

0

1 (3.1)

1 (5.0)

2 (2.0)

0

2 (0.5)

Total

16 (32.0)1

27 (84.3)

17 (85.0)2

60 (58.8)3

128 (42.1)

188 (46.3)

Notes:

*CKD — chronic kidney disease; CVDs — cardiovascular diseases; CHF — chronic heart failure; GFR — glomerular filtration rate

 1— the differences are sensitive (p < 0.05) between the number of patients with CHF stages I and IIA;

2the differences are sensitive (p < 0.05) between the number of patients with CHF stages IIA and IIB;

3 — the differences are sensitive (p < 0.05) between the number of patients with CHF stage IIB and patients with CVDs complicated by CHF;

4the differences are sensitive (p < 0.05) between the groups of patients with CVDs complicated and uncomplicated CHF.

As it can be seen from Table 1, CKD stage II was observed in 41.1% of cases in the general sampling, 40.5% of patients without CHF, and 43.1% of patients with CHF. An acute reduction of renal function was registered in 4 (1.0%) patients. CKD stage IV (during one of the repeated hospitalizations) developed in 1 (0.25%) patient. In patients with CHF stages I and IIA, an insignificant reduction of GFR was revealed in 13 (26.0%) and 21 (65.6%) cases, respectively. In patients with CHF stage IIB, their share was lower (10 (50.0%) patients), and thus, the share of patients with moderately reduced renal filtration capacity (5.0–25.0%) was higher. An acute reduction of GFR was registered only in 1 (2.0%) patient with CHF stage I, and in 2 patients (6.2%) and 1 patient (5.0%) with CHF stages IIA and IIB, respectively.

Out of 52 patients included in the second part of the study, the ratio of men and women was 41/11 (78.8% and 21.2%, respectively). In all three groups, male patients prevailed: 13 (72.2%), 13 (86.65%), and 15 (78.9%), respectively. In group I, by the beginning of the study, all patients were older than 60 years old (and 10 of them were older than 70 years old). In group II and the control group, patients aged 50–59 years old prevailed. In group III, 2 patients were younger than 40 years old. Six of them did not survive until 50 years old. EHT stage I was observed in 1 patient (2 – in group II, the rest – in the control group). EHT stage II was diagnosed in 21 patients (13 – in group I and 8 – in group II). EHT stage III was revealed in 12 patients (7 – in group I, all patients in the group with stage IIB CHF, 5 – in group II, and 1 – in the control group). Atherosclerotic cardiosclerosis registered in the medical records of 35 (67.3%) respondents, atherosclerosis of aorta – in 27 (51.9%) respondents, and postinfarction cardiosclerosis – in 13 (25.0%) patients. In 6 (11.5%) patients, heart rhythm disturbance was observed; in 3 patients (5.8%), acquired heart valvular disease was registered. One kidney was affected in 21 (40.4%) patients, both kidneys – in 4 (7.7%) patients; one ureter – in 16 (30.8%) patients, and both ureters – in 1 (1.9%). Stones in the kidneys and ureters were observed in 11 (21.1%) patients. The results of the evaluation of renal filtration functioning in dynamics (within a 10-year follow-up) are presented in Table 2.

Table 2. Dynamics of glomerular filtration rate (M ± m) in patients with ischemic heart disease and hypertension (n = 52), depending on the presence of chronic heart failure

Research period

Patient groups

I (n = 18)

II (n = 15)

III (n = 19)

Study origin

74.9 ± 2.41

79.8 ± 1.5

82.5 ± 1.4

After 2 years

 67.0 ± 1.61,4

77.6 ± 1.92

81.7 ± 0.9

After 4 years

61.9 ± 2.71

  74.7 ± 0.32,5

80.7 ± 1.53

After 6 years

49.7 ± 2.91

68.7 ± 1.82

  77.2 ± 2.23,6

After 8 years

38.9 ± 1.51

59.8 ± 3.92

72.8 ± 2.13

After 10 years

31.7 ± 3.21

48.5 ± 4.62

64.3 ± 1.73

Notes:

*blue — CKD stage II (slight decrease in glomerular filtration rate); grey — CKD stage III Ca (moderately reduced kidney function); green — CKD stage III Cb (sharply reduced kidney function).

1 the differences between groups I and III are sensitive (p < 0.05);

2 the differences between groups I and II are sensitive (p < 0.05);

3 the differences between groups II and III are sensitive (p < 0.05);

4the first sensitive (p < 0.05) difference between the initial value and the subsequent ones for group I;

5 the first sensitive (p < 0.05) difference between the initial value and the subsequent ones for group II;

6 the first sensitive (p < 0.05) difference between the initial value and the subsequent ones for group III.

Initially, GFR in patients from group I was significantly different from the GFR in the control group. A similar difference in patients from group II appeared 4 years after the beginning of the study. A significant difference from the group I developed already after 2 years. An acute (by 1.5 times) significant decrease in the renal filtration function was registered in group I by the 6th year of the study, in group II (by 1.3 times) – by the 8th year, and in group III (by 1.28 times) – by the 10th year. In group I, by the 10th follow-up year, the level of GFR reduced by 2.36 times, and in group II, by 1.65 times.

Discussion

In the present study, patients had all possible causes for the formation of CKD: long-term recurrence inflammatory process in the renal tissues, obstruction, nephroangiosclerosis, and post-traumatic renal parenchyma injury. Long-term observation after patients attached to the military hospital allowed the authors to evaluate the rate of CKD progression. Initially, GFR was insignificantly reduced in all three groups, was of a similar level, and corresponded to CKD stage II.

As it was mentioned before, minimal values of creatinine (within the current hospitalization) were taken for the estimations to minimize the errors because the applied method of GFR was applied to a “typical” patient. This method did not exclude completely a component of acute reduction of glomerular filtration but revealed a general tendency. If a typical patient has recurrent nephrolithiasis and CKD stage II (i.e. moderately expressed, clinically insignificant GFR), a progression of renal function defect is quite slow. Within the first years, provided there are no severe complications (for example, purulent destructive pyelonephritis) and associated diseases, there may be no progression. Renal function remains moderately and consistently reduced with insignificant fluctuations in the GFR around 80 ml/min within 2 years. After that, the rate of GFR reduction significantly increases (4.5 ml/min per year in 5 years).

In old classifications of chronic kidney disease proposed by Tareev (1982) and Lopatkin (1973), such status of renal filtration function was considered to be normal. A progressing reduction of GFR develops 5–6 years after the diagnosis of CKD stage II in a patient. A decrease in GFR is slow. On average, it reduced by 10 ml/min in 8 years. Further, the rate of pathological process development increases to 7 ml/min per year. In general, CKD stage II is observed for 10 years in a typical patient with nephrolithiasis without CVDs and initial GFR = 80 ml/min. To compare, in a patient with diabetic nephropathy (in case of natural disease development or lack of therapy), a decrease in GFR is 1 ml/min per month or 10–12 ml/min per year, i.e. tissues are affected 2.7 times faster [28].

When CHF stage I is added, there is no period when the renal function changes insignificantly, and the rate of a decrease in GFR is 4–5 ml/min per year. A patient with EHT + IHD complicated by CHF stage I and initial GFR = 7 ml/min reaches CHF stage III in 4 years. If this patient lives for 6 more years without life-threatening complications, CKD is likely to develop into stage IV. Otherwise, in 6 years, a patient with recurrent nephrolithiasis and CKD stage II without concomitant CVDs will have GFR reduced by 5.3 ml/min; a patient with combined nephrolithiasis and CVDs (EHT + IHD) – by 11.1 ml/min; and a patient with CVDs initially complicated by CHF – by 25.2 ml/min.

If filtration deficiency progresses slowly, a severe form of CKD in patients with nephrolithiasis is observed rarely and does not provide a significant issue. Partially, this is true. Among the cause of terminal CKD, the rate of calculous pyelonephritis is much lower than the rate of chronic glomerulonephritis, diabetic nephropathy, and nephroangiosclerosis [5]. However, in real urological practice, the number of patients with nephrolithiasis and kidney disease is high. This fact can be explained simply: before a significant reduction of the volume of patent parenchyma and hyperfiltration, calculous pyelonephritis progresses via the episodes of activity and recurrence of acute conditions. The study aimed to evaluate renal function in patients with “planned” development of the disease without urgent episodes (nephrectomy, purulent destructive pyelonephritis, acute renal injury). Still, one long-term “attack” of pyelonephritis can provoke nephrosclerosis that expression would be comparable to several years of the slow development of nephrolithiasis with periodic episodes of distant or contact stone fragmentation, kidney drainage, etc.

Conclusions

  1. A decrease in GFR was registered in 46.3% of patients with recurrent stone kidney disease, 42.1% of patients with combined recurrent nephrolithiasis and CVDs (IHD, EHT, IHD + EHT), and 60 (58.8%) patients with CHF of various severity. GFR reduction that corresponded to CHF stage II was registered in 41.1%, 40.5%, and 43.1%, respectively.
  2. In patients with CHF stages I and IIA, an insignificant decrease in GFR was observed in 13 (26.0%) and 21 (65.6%) of cases. The share of patients with CHF stage II was lower (10 (50.0%)), and thus, the share of patients with moderately reduced renal filtration function was higher (5.0– 25.0%).
  3. CKD in patients with recurrent stone kidney disease in combination with IHD and EHT is benign: the rate of filtration deficit progressing is comparatively low and equals around 4.5 ml/min per year (at least, at early stages).
  4. Concomitant CHF increases the rate of renal filtration function reduction to 25.0% (from 4 ml/min per year to 5 ml/min per year).
  5. The main negative influence of concomitant CVDs (especially, complicated by CHF) is not in the ultra-high decrease in GFR but the reduction (until complete cessation) of a stable period of renal functioning.

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About the Authors

R. V. Royuk
Burdenko Principal Military Clinical Hospital
Russian Federation

Ruslan V. Royuk – M.D., Сand.Sc.(Med); Head, Urology Division

105094, Moscow, 3 Hospitalnaya sq.


Competing Interests:

The authors declare no conflicts of interest.



S. K. Yarovoy
Lopatkin Scientific Research Institute of Urology and Interventional Radiology – National Medical Research Radiologiсal Centre Branch; Pletnev City Clinical Hospital – Moscow City Healthcare Department
Russian Federation

Sergey K. Yarovoy – M.D., Dr.Sc.(Med), Full Prof.; Chief Researcher, Clinical Pharmacologist Lopatkin Scientific Research Institute of Urology and Interventional Radiology – National Medical Research Radiologiсal Centre Branch; Clinical Pharmacologist; Pletnev City Clinical Hospital – Moscow City Healthcare Department Moscow

105425, Moscow, 51 bldg. 1 3rd Parkovaya st.

105077, Moscow, 32 11th Parkovaya st.


Competing Interests:

The authors declare no conflicts of interest.



For citation:


Royuk R.V., Yarovoy S.K. Chronic kidney disease in patients with recurrent nephrolithiasis and concomitant damage to the cardiovascular system. Vestnik Urologii. 2021;9(3):52-61. (In Russ.) https://doi.org/10.21886/2308-6424-2021-9-3-52-61

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