Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients' survival.

BACKGROUND: Comorbidities are associated with increased mortality among patients receiving long-term kidney replacement therapy (KRT). However, it is not known whether primary kidney disease modifies the effect of comorbidities on KRT patients' survival.
METHODS: An incident cohort of all patients (n = 8696) entering chronic KRT in Finland in 2000-2017 was followed until death or end of 2017. All data were obtained from the Finnish Registry for Kidney Diseases. Information on comorbidities (coronary artery disease, peripheral vascular disease, left ventricular hypertrophy, heart failure, cerebrovascular disease, malignancy, obesity, underweight, and hypertension) was collected at the start of KRT. The main outcome measure was relative risk of death according to comorbidities analyzed in six groups of primary kidney disease: type 2 diabetes, type 1 diabetes, glomerulonephritis (GN), polycystic kidney disease (PKD), nephrosclerosis, and other or unknown diagnoses. Kaplan-Meier estimates and Cox regression were used for survival analyses.
RESULTS: In the multivariable model, heart failure increased the risk of death threefold among PKD and GN patients, whereas in patients with other kidney diagnoses the increased risk was less than twofold. Obesity was associated with worse survival only among GN patients. Presence of three or more comorbidities increased the age- and sex-adjusted relative risk of death 4.5-fold in GN and PKD patients, but the increase was only 2.5-fold in patients in other diagnosis groups.
CONCLUSIONS: Primary kidney disease should be considered when assessing the effect of comorbidities on survival of KRT patients as it varies significantly according to type of primary kidney disease.

Introduction

Many of the patients entering long-term kidney replacement therapy (KRT) have other medical conditions as well [1,2]. In addition, cause of kidney failure is associated with the frequency of comorbidities; for instance, KRT patients with diabetic nephropathy have more comorbidities than patients with other causes of kidney disease [3,4].

Several studies have shown that the effect of both comorbidities and of primary kidney disease is significant on KRT patients’ survival [5,6]. However, Van Manen et al. [7] reported that adding comorbidities to a multivariable model on top of primary kidney disease and general patient characteristics had only a small impact on hazard ratios of death. Nevertheless, all published models predicting risk of death for patients starting dialysis assume that the effect of comorbidities on survival is constant despite primary kidney disease [8].

Knowledge on whether primary kidney disease modifies the effect of comorbidities on survival is scarce or nonexistent. This study shows how comorbidities are associated with mortality according to primary kidney disease.

Materials and methods

All data were obtained from the Finnish Registry for Kidney Diseases. This registry has 97–99% coverage of all Finnish patients on chronic KRT since 1965. The registry is maintained by the Finnish Liver and Kidney Association and financed by the Finnish government. All patients aged 18 years or older who entered chronic KRT in an outpatient setting from 1 January 2000 to 31 December 2017 were included in the study (n = 8696). Information on age at start of KRT, sex, cause of kidney disease coded using ICD-10 codes, type of KRT (hemodialysis, peritoneal dialysis, or kidney transplantation), and time and cause of death were collected. Data on comorbidities (coronary artery disease, peripheral vascular disease, left ventricular hypertrophy, heart failure, cerebrovascular disease, and malignancy) had been collected at start of KRT as well as data on blood pressure and body mass index (BMI). The cut-off value for obesity was set at BMI >30 kg/m2 and for underweight at BMI <20 kg/m2.

The patients were followed from the start of KRT until death (55.1%), loss to follow-up (0.1%), moving abroad (0.2%), recovery of kidney function (1.9%), or end of follow-up on 31 December 2017 (42.7%). We divided the patients into six groups according to their primary kidney disease: type 2 diabetes, type 1 diabetes, glomerulonephritis (GN), polycystic kidney disease (PKD), nephrosclerosis, and other or unknown diagnoses. Information on comorbidities was available for 89% (left ventricular hypertrophy) to 97% (coronary artery disease) of patients. Information on all comorbidities was available for 85% of patients. Multiple imputation was used for sensitivity analyses.

The Finnish Registry for Kidney Diseases collects written informed consent from all patients for use of data for research purposes. The nephrological centers in Finland provide data on all patients at start of chronic KRT and once a year thereafter to the Finnish Registry for Kidney Diseases and these patient records are stored in the registry database. This study was approved by the Board of the Finnish Registry for Kidney Diseases and conducted in accordance with the Data Protection Law. The patient records used here were pseudonymized, the data were encrypted, and only specified persons of the research group had access to the database. Thus, individuals cannot be identified from the results, and the study was based entirely on previously collected registry data. The dataset for this study was retrieved from the database of the Finnish Registry for Kidney Diseases in November 2018.

Statistical methods

Between-group comparisons were performed using χ2 test for categorical variables and the Kruskal-Wallis test for continuous variables. Survival probabilities were calculated using Kaplan-Meier curves, and differences between groups were assessed using the log-rank test. Relative risks of death as a function of comorbidity were estimated using Cox proportional hazards regression with and without adjustment for potential confounding factors. Death was the event and patients were censored at the last day of follow-up or at the latest on 31 December 2017. Patients were not censored at kidney transplantation in the main analyses. Interactions between diagnosis group and comorbidities were assessed by including interaction terms in Cox regression with and without adjustment to determine whether the effect of comorbidity on survival differs according to diagnosis group. Two-sided p values lower than 0.05 were considered significant.

Statistical analyses were performed using SPSS Statistics, version 25.0.

Results

Baseline characteristics

Of the 8696 patients (41 793 patient-years), 4793 died during follow-up. Table 1 presents baseline characteristics, follow-up, and survival by diagnosis group. Median age at start of KRT was the lowest, 47.3 years, among patients with type 1 diabetes and the highest, 72.7 years, among patients with nephrosclerosis. Median survival time of all patients was 5.4 years, ranging from 3.3 years in patients with type 2 diabetes to 15.4 years in patients with PKD. The most common cause of death was cardiovascular disease, accounting for 42% of the deceased patients. Hemodialysis was the initial treatment modality in 75% and peritoneal dialysis in 25% of patients. Of all patients, 2% started in home hemodialysis and 33% received a kidney transplant during follow-up.

Table 1

Baseline characteristics, follow-up, and survival according to primary kidney disease.

	Type 2 diabetes	Type 1 diabetes	Glomerulo-nephritis	Polycystic kidney disease	Nephro-sclerosis	Other or unknown diagnoses	All patients	P value
Number of patients (%)	1720 (19.8)	1315 (15.1)	1207 (13.9)	826 (9.5)	539 (6.2)	3089 (35.5)	8696 (100)
Kidney biopsy, %	13.5	7.6	86.7	1.8	27.9	29.1	28.3	<0.001
Male gender, %	69.0	65.5	71.6	51.7	72.7	62.8	65.2	<0.001
Median age at KRT start in years (25 th –75 th percentile)	67.0 (60.5–73.0)	47.3 (39.2–55.6)	59.7 (46.8–69.2)	57.9 (51.1–64.8)	71.8 (62.5–78.5)	67.5 (56.3–75.8)	63.2 (51.6–72.2)	<0.001
Median follow–up time in years (25 th –75 th percentile)	2.65 (1.28–4.78)	3.87 (1.68–8.61)	5.00 (1.97–9.56)	5.97 (2.78–10.58)	2.67 (1.21–5.16)	2.95 (1.12–6.20)	3.41 (1.41–7.02)	<0.001
Hemodialysis as the first treatment modality, %	83.1	55.6	68.2	77.7	76.1	81.1	75.2	<0.001
Kidney transplantation during follow-up, N (N/100 patient-years)	186 (3.1)	628 (8.7)	609 (8.1)	557 (9.6)	105 (5.1)	739 (5.6)	2824 (6.8)	<0.001
Median survival in years (95% CI)	3.26 (3.08–3.43)	7.95 (6.83–9.07)	12.23 (10.88–3.57)	15.41 (N/A)	4.02 (3.53–4.51)	4.45 (4.19–4.72)	5.39 (5.18–5.60)	<0.001
Number of deaths (N/100 patient-years)	1294 (21.6)	619 (8.6)	445 (5.9)	236 (4.1)	342 (16.7)	1857 (14.0)	4793 (11.5)	<0.001
Cardiovascular cause of death, %	46.8	57.0	44.0	37.7	45.3	31.8	41.5	<0.001

95% CI, 95% confidence interval.

More than half of the patients had at least one comorbidity (coronary artery disease, peripheral vascular disease, left ventricular hypertrophy, heart failure, cerebrovascular disease, or malignancy). Left ventricular hypertrophy (in 33%) and coronary artery disease (in 25%) were the most common comorbidities. Patients with type 2 diabetes or nephrosclerosis as the cause of kidney failure had significantly more comorbidities than other patients, and the number of comorbidities was the lowest in patients with PKD. Obesity was more common in those with type 2 diabetes than in other groups. Systolic blood pressure was elevated in two-thirds and diastolic blood pressure in one-quarter of patients despite the high prevalence of medication for hypertension (Table 2).

Table 2

Proportion of patients with comorbidities and medication at start of KRT according to primary kidney disease.

%	Type 2 diabetes	Type 1 diabetes	Glomerulo–nephritis	Polycystic kidney disease	Nephro–sclerosis	Other or unknown diagnoses	All patients	P value
Coronary artery disease	41.2	24.5	14.1	10.7	39.2	22.3	25.2	<0.001
Peripheral vascular disease	28.8	20.2	4.7	4.2	25.2	10.2	15.0	<0.001
Left ventricular hypertrophy	48.3	33.2	26.4	21.9	51.3	27.2	33.0	<0.001
Cerebrovascular disease	16.9	11.9	9.0	9.6	15.5	8.6	11.3	<0.001
Heart failure	19.5	7.3	5.2	2.1	14.2	10.7	10.5	<0.001
Malignancy	9.9	3.5	8.0	6.5	14.3	19.8	12.1	<0.001
One comorbidity a	30.1	29.4	27.4	27.4	33.3	32.2	30.3	<0.001
Two comorbidities a	24.2	15.4	10.6	8.9	21.7	14.9	16.1	<0.001
Three or more comorbidities a	22.6	10.8	4.9	2.7	22.4	10.0	12.0	<0.001
Obesity (BMI > 30 kg/m 2 )	47.5	16.4	23.1	17.4	19.1	16.7	23.9	<0.001
Underweight (BMI < 20 kg/m 2 )	1.8	6.5	6.4	4.2	4.8	8.6	6.0	<0.001
Systolic blood pressure > 140 mmHg	72.4	76.7	68.3	62.6	69.7	56.4	65.7	<0.001
Diastolic blood pressure > 90 mmHg	15.5	31.0	35.5	31.2	22.6	20.2	24.3	<0.001
Medication for hypertension	95.0	96.6	94.0	92.5	95.6	78.2	88.9	<0.001
Medication for dyslipidemia	73.7	71.5	55.2	45.4	58.4	38.0	54.6	<0.001

BMI, body mass index.

aOf the six comorbidities above.

Comorbidities and relative risk of death

Without adjustment, all comorbidities, obesity, and underweight were associated with increased risk of death, and only elevated blood pressure was associated with decreased risk of death regardless of whether patients were on medication for high blood pressure. The relative risk of death that was associated with each comorbidity varied significantly according to primary kidney disease. Relative risk of death associated with presence of heart failure varied the most, from 1.91 (95% CI 1.66–2.19) in patients with type 2 diabetes to 6.61 (95% CI 3.57–12.22) in patients with PKD, when the risk of death was compared with patients who did not have heart failure within the same diagnosis group (S1 Table).

When adjusted for age and sex, primary kidney disease significantly modified the effect of coronary artery disease, heart failure, and malignancy on death, as all of these increased risk of death more in PKD and GN patients than in other patients (S2 Table). Obesity was associated with increased risk of death only in patients with GN. Underweight was also associated with worse prognosis, especially among patients with type 1 diabetes or nephrosclerosis.

In the multivariable model (Table 3), coronary artery disease, heart failure, and higher age had the strongest effect on worse prognosis in patients with GN or PKD. Malignancy had the most marked worsening effect on prognosis in patients with PKD. Similar to the less adjusted model, in our multivariable model the risk of death that was associated with underweight was the highest in patients with type 1 diabetes, and obesity was associated with worse prognosis only in GN patients.

Table 3

Multivariable model of comorbidities’ effect on relative risk of death according to primary kidney disease.

Comorbidity, RR (95%CI)	Type 2 diabetes	Type 1 diabetes	Glomerulo-nephritis	Polycystic kidney disease	Nephro-sclerosis	Other or unknown diagnoses	All patients	Interaction P valuea
Coronary artery disease	1.18 (1.02–1.36)	1.04 (0.85–1.26)	1.58 (1.21–2.07)	1.79 (1.21–2.66)	1.09 (0.81–1.46)	1.19 (1.04–1.36)	1.29 (1.19–1.40)	<0.001
Peripheral vascular disease	1.80 (1.55–2.08)	1.67 (1.32–2.11)	1.24 (0.81–1.89)	1.64 (0.97–2.77)	1.47 (1.09–1.97)	1.26 (1.07–1.50)	1.64 (1.50–1.79)	0.215
Left ventricular hypertrophy	1.01 (0.88–1.15)	1.10 (0.90–1.35)	1.17 (0.92–1.48)	1.11 (0.79–1.56)	1.14 (0.86–1.50)	1.11 (0.99–1.26)	1.13 (1.05–1.22)	0.070
Cerebrovascular disease	1.15 (0.97–1.37)	1.28 (0.97–1.67)	1.52 (1.08–2.14)	1.08 (0.68–1.72)	1.34 (0.93–1.92)	1.26 (1.07–1.50)	1.24 (1.12–1.36)	0.581
Heart failure	1.41 (1.19–1.67)	1.81 (1.29–2.54)	3.18 (2.10–4.83)	3.05 (1.46–6.36)	1.87 (1.28–2.72)	1.85 (1.56–2.18)	1.83 (1.65–2.03)	<0.001
Malignancy	0.92 (0.74–1.15)	1.42 (0.91–2.21)	1.34 (0.97–1.86)	1.92 (1.18–3.11)	0.72 (0.51–1.03)	1.20 (1.06–1.36)	1.18 (1.07–1.29)	<0.001
Normal weight (BMI 20–30 kg/m 2 )	1	1	1	1	1	1	1	0.002
Obesity (BMI > 30 kg/m 2 )	0.95 (0.83–1.08)	1.05 (081–1.36)	2.04 (1.59–2.61)	0.87 (0.59–1.29)	0.85 (0.61–1.20)	0.98 (0.85–1.13)	1.14 (1.05–1.22)
Underweight (BMI < 20 kg/m 2 )	1.15 (0.70–1.88)	2.11 (1.52–2.95)	1.43 (0.93–2.21)	1.45 (0.77–2.73)	1.35 (0.74–2.46)	1.54 (1.30–1.83)	1.53 (1.35–1.74)
Systolic blood pressure > 140 mmHg	0.74 (0.64–0.85)	0.83 (0.66–1.04)	0.96 (0.76–1.23)	1.07 (0.78–2.73)	1.11 (0.82–1.50)	0.89 (0.79–0.99)	0.94 (0.87–1.01)	0.325
Diastolic blood pressure > 90 mmHg	0.90 (0.75–1.09)	1.00 (0.79–1.27)	0.89 (0.67–1.18)	0.85 (0.60–1.20)	0.77 (0.55–1.08)	1.03 (0.89–1.20)	0.88 (0.80–0.96)	0.060
Age at start (per 10 years increment)	1.45 (1.34–1.57)	1.42 (1.28–1.57)	2.29 (2.04–2.58)	2.11 (1.78–2.51)	1.87 (1.61–2.17)	1.63 (1.56–1.72)	1.62 (1.57–1.67)	<0.001
Female sex	1.15 (0.98–1.32)	1.04 (0.85–1.26)	1.02 (0.79–1.31)	0.85 (0.63–1.15)	0.85 (0.63–1.14)	1.08 (0.97–1.21)	1.00 (0.93–1.07)	0.593

aInteraction between diagnosis group and comorbidity.

RR, relative risk of death; 95% CI, 95% confidence interval; BMI, body mass index.

Separate multivariable models were made for each diagnosis group (in columns) including all comorbidities in the table.

Patients for whom we had all comorbidity data had better survival than patients with non-complete comorbidity data, and median survival times were 5.57 (95% CI 5.32–5.82) years and 4.63 (95% CI 4.25–5.01) years, respectively. Multiple imputation of missing comorbidity data did not change our results. When patients were censored at time of kidney transplantation, the differences in comorbidities’ association with risk of death according to primary kidney disease remained similar to results without censoring at kidney transplantation.

Number of comorbidities and risk of death

Six comorbidities (coronary artery disease, peripheral vascular disease, left ventricular hypertrophy, heart failure, cerebrovascular disease, and malignancy) were included in the survival analyses on number of comorbidities. Increasing number of comorbidities was associated with higher risk of death in all primary kidney disease groups, but after adjustment for age and sex, the increase was more significant among patients with GN or PKD. Three or more comorbidities, compared with no comorbidity, increased risk of death 4.62-fold in patients with GN and 4.36-fold in patients with PKD, whereas relative risk varied from 2.25 to 2.63 in other primary kidney disease groups (S3 Table). Furthermore, survival time varied markedly in primary kidney disease groups according to number of comorbidities. In patients without comorbidities, median survival ranged from 4.9 years (patients with type 2 diabetes) to more than 18 years (PKD patients). However, if patients had three or more comorbidities the variation in median survival time was much smaller: from 1.5 years in GN patients to 2.9 years in PKD patients (Fig 1). This also indicates that the number of comorbidities is more relevant to the survival prognosis in patients with PKD and GN than in other diagnostic groups.

Fig 1

Effect of the number of comorbidities on unadjusted survival probability according to primary kidney disease.

Discussion

Our study shows that comorbidities affect KRT patients’ risk of death differently depending on the type of primary kidney disease. This study included all adult patients who entered long-term KRT during 2000–2017 in Finland. A significantly greater increase in risk of death was seen in PKD and GN patients with heart failure, coronary artery disease, or malignancy than with other diagnoses, when comparing patients in the same diagnosis group with or without these comorbidities. PKD or GN patients diagnosed with heart failure before start of KRT showed a fivefold age- and sex-adjusted risk of death relative to those without this comorbidity, whereas among patients with other primary kidney diseases the increase was only twofold. PKD and GN patients had less comorbidities and better survival than other KRT patients. However, if these patients had multiple comorbidities their survival was similar to other patients with multiple comorbidities due to the greater effect of comorbidities in the survival prognosis in patients with PKD or GN than in patients with other diagnoses. To our knowledge, no previously published study has assessed this primary kidney disease-related variation in comorbidities’ effect on mortality.

This nationwide study included all patients starting KRT in Finland during the 18-years study period. Data on mortality were complete, the number of patients lost to follow-up was very low, data were collected in a similar manner throughout the study period, and data on the most important comorbidities were available for a large proportion of patients. Therefore, the possibility of selection or information bias was minimal. However, a few limitations should be noted. The population in Finland is genetically quite homogeneous and almost entirely white, which may reduce the generalizability of the findings. Another potential limitation is that comorbidity data were collected mainly from pre-existing information, that is, patients were not examined separately for registry purposes. This could cause reporting bias since more severe cases were more likely reported. We also had no information on severity of comorbidities. Results of a study from the Netherlands, however, showed that adding severity grading of several comorbid conditions did not lead to improved prognostic power [9]. Although we did not have complete information on comorbidities, the data we used were significantly more comprehensive in this respect than the data used in some previous registry studies [5,10,11].

Generally, when comparing the results of our study with results of earlier ones from other countries, it is crucial that diagnoses of primary kidney disease groups and classification of comorbid conditions are comparable. Diabetes is the leading cause of end-stage kidney disease (ESKD) in most of the countries, but incidence of ESKD caused by type 1 diabetes is higher in Finland than in other countries. The ERA-EDTA Registry, the United States Renal Data System, and previous studies have reported higher proportions of incident KRT patients with hypertension or renal vascular disease as the cause of kidney disease than we report here [5,7,12,13]. Some of the differences may emerge from differences between populations, but also classification of primary kidney disease may differ. Definitions of comorbidities and methods of data collection are likely to have an impact on reported numbers of comorbidities. Previous studies have described a higher incidence of peripheral vascular disease and heart failure at the start of KRT, whereas incidence of coronary artery disease, cerebrovascular disease, and malignancies has been similar to our study [2,4,5,7,14].

All six major comorbidities reported here have also earlier been shown to be associated with increased mortality [2,6,14-16]. Of note, van Manen et al. [7] showed that the influence of comorbidities may be less important than expected, explaining only 1.9% of the variance in mortality. Underweight has previously been established to be associated with an increased risk of death, but the association between obesity and mortality among GN patients shown here, has not been published earlier [17-20]. Although treatment of hypertension reduces mortality among patients on hemodialysis [21], hypertension has been demonstrated to have an inverse association with mortality in epidemiological studies [6,22], which is in line with our results. This may be due to an increased risk of death associated with intradialytic hypotension [23]. Taken together, our results on the entire KRT population resemble those of previous studies, and this supports the generalizability of our findings on how primary kidney disease modifies the effect of comorbidities on survival.

How could the results of our study be interpreted? Lower age in GN and PKD patients could be one explanation. If malignancy is diagnosed at a younger age, it is more likely to be more aggressive than among older patients, thus worsening the prognosis more in a young population. In addition, conservative treatment for ESKD may have been chosen more often for elderly patients who have malignancy with a poor prognosis. However, although patients with type 1 diabetes in our study were younger than GN and PKD patients, their risk of death associated with malignancy was lower. Lower risk of malignancy-related mortality in patients with diabetes than in patients with GN has been reported previously and may be caused by a higher risk of cardiovascular death in patients with diabetes as a competing factor [24]. Cardiovascular morbidity is high in patients with diabetes and in elderly patients and some of these patients may have undiagnosed coronary artery disease and heart failure. Consequently, had some of these patients been misclassified as not having these comorbidities, this would have diluted the association with comorbidity and mortality and could explain the stronger association with mortality in GN and PKD patients. In addition, higher overall risk of death in patients with diabetes and in elderly patients may reduce the additional effect of comorbidities on mortality. Furthermore, severity and type of comorbid disease at time of diagnosis and the different treatments for these comorbidities may have influenced our results.

In conclusion, comorbidities affect KRT patients’ survival differently depending on the type of primary kidney disease. When assessing prognosis of patients with GN or PKD, especially cardiological problems and malignancies should be taken into account. Our findings should be considered when building prognostic models that include comorbidities, because otherwise these models are not accurate, and the estimates calculated with these models may lead to wrong conclusions for some patients. Future studies could shed more light on potential differences in severity or nature of comorbidities according to primary kidney disease. To avoid known shortcomings of an observational study like ours, a randomized study could reveal whether systematic screening and treatment of comorbidities in patients starting KRT would improve their survival.

Unadjusted effect of comorbidities on relative risk of death according to primary kidney disease.

(DOCX)

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Age- and sex-adjusted effect of comorbidities on relative risk of death according to primary kidney disease.

(DOCX)

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Age- and sex-adjusted relative risk of death according to the number of comorbidities in various groups of primary kidney disease.

(DOCX)

Click here for additional data file.

17 Mar 2021

PONE-D-20-35936

Primary renal disease modifies the effect of comorbidities on renal replacement therapy patients’ survival

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Editors,

Thank you for inviting me to review this manuscript.

This manuscript is well written with a few minor revisions. The authors were able to address the issue on whether primary renal disease modifies the effect of comorbidities on the survival of patients on chronic dialysis therapy. If published, I think this will guide clinicians make management decisions especially on how often they need to follow up with a patient. This will also help in prognostication as their data showed that patients with glomerulonephritis and polycystic kidney disease have higher risk of mortality if they have coronary artery disease or heart failure compared to other patients.

I do have some points that I would like some clarification or need some revision.

1. Their definition of overweight was a BMI > 30. Based on current criteria by the WHO, being overweight is defined as a BMI of 25.0 to <30. It might be better if they change the term overweight to obesity instead.

2. Their definition of underweight was BMI <20. Based on current criteria by the WHO, being underweight is defined as a BMI of < 18.5. However, I acknowledge that this might potentially impact their results if they adjust the cut-off. My concern is that it may misinform the readers if they used different cut-off criteria.

3. I would like to know the rationale for not including hypertension as one of the 6 comorbidities. As I compared the data from Table 2 and Table 3, it appears that they looked at patients who had elevated blood pressures and patients who were on anti-hypertensive medications. The total proportion of patients on medication was 88.9% while those with high blood pressure was 65.7% for those with elevated SBP and 24.3% for those with elevated DBP. It would be helpful for the readers to know if patients who were diagnosed with hypertension, whether controlled or not, and whether on medication or not had any significant difference in mortality.

4. The authors need to revise the language especially in the discussion part to improve readability. The specific part that needs revision is found on line 180-181, line 209-210.

Sincerely,

Carissa Dumancas, MD

Reviewer #2: The authors have described "Primary renal disease modifies the effect of comorbidities on renal replacement therapy patients’ survival". After reading the manuscript thoroughly, i suggest following modifications.

1) Authors include good cohort of RRT patients and studied retrospectively. Can authors kindly explain if its done outpatient setting only or have included patients with continuous renal replacement therapies while in hospital too.

2) Can authors mention if only hemodialysis patients were included / or patients on home therapies were included too as that could change the effect of co morbidities and primary disease on mortality.

3) Table-1 indicates that among pts with polycystic kidney disease, significant number 9.6 % underwent renal transplant as compared to type 2 DM with 3.1%. Can authors elaborate if that has any potential impact on over all mortality .

4) Table-2 indicates that most of the co morbidities including CAD, peripheral vascular disease, left ventricular hypertrophy, more than 3 Co morbidities is highest among Type 2 DM and patients with Nephrosclerosis, which in turn correlate with increased mortality. However in the results sections, authors concluded that Polycystic kidney disease, GN are associated with increase mortality. How do authors explain this variation.

5)Multiple studies mentioned uncontrolled hypertension as independent risk of mortality among ESRD patients on RRT. However the results are the study are opposite. Can authors elaborate on this

6) Appears that majority on patients in Finland are white population and hence these results could not be generalized to other parts of world with predominant black / asian population. Would be interesting to see sub group analysis on older age and race if they preset with similar findings.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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17 Apr 2021

The authors’ detailed response to the Additional Editors and Reviewers comments on the manuscript “Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients’ survival”

Additional Editor Comments:

Manuscript is of interest in the Nephrology community. It is a large cohort of patients in Finland looking at the effect of comorbidities by primary kidney disease modifying survival in patients on dialysis.

Also, please modify "renal" to "kidney" throughout the manuscript, whenever it is possible to refer to kidney disease or kidney function, as it is the new terminology recommendation by the KIDGO and to make it more patient-centered.

Authors’ reply: Thank you for this notice. We have now modified the manuscript and replaced “renal” to “kidney”.

In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study, including the date range (month and year) during which patients' medical records/samples were accessed.

Authors’ reply: We have added this more detailed information about patient records to the Materials and methods (page 5, lines 79–81 and page 6, lines 85–86).

We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly.

Authors’ reply: Our data are retrieved from the patient-level data and the sharing is restricted by the EU General Data Protection Regulation 2016/679.

Reviewer #1:

This manuscript is well written with a few minor revisions. The authors were able to address the issue on whether primary renal disease modifies the effect of comorbidities on the survival of patients on chronic dialysis therapy. If published, I think this will guide clinicians make management decisions especially on how often they need to follow up with a patient. This will also help in prognostication as their data showed that patients with glomerulonephritis and polycystic kidney disease have higher risk of mortality if they have coronary artery disease or heart failure compared to other patients.

I do have some points that I would like some clarification or need some revision.

1. Their definition of overweight was a BMI > 30. Based on current criteria by the WHO, being overweight is defined as a BMI of 25.0 to <30. It might be better if they change the term overweight to obesity instead.

Authors’ reply: Thank you for this comment. We agree that obesity is better term for BMI > 30 and we have now changed this in the manuscript.

2. Their definition of underweight was BMI <20. Based on current criteria by the WHO, being underweight is defined as a BMI of < 18.5. However, I acknowledge that this might potentially impact their results if they adjust the cut-off. My concern is that it may misinform the readers if they used different cut-off criteria.

Authors’ reply: We acknowledge this potential misinformation and we have now clarified this in the Methods (page 5, lines 68–69).

3. I would like to know the rationale for not including hypertension as one of the 6 comorbidities. As I compared the data from Table 2 and Table 3, it appears that they looked at patients who had elevated blood pressures and patients who were on anti-hypertensive medications. The total proportion of patients on medication was 88.9% while those with high blood pressure was 65.7% for those with elevated SBP and 24.3% for those with elevated DBP. It would be helpful for the readers to know if patients who were diagnosed with hypertension, whether controlled or not, and whether on medication or not had any significant difference in mortality.

Authors’ reply: We did not include hypertension as one of the comorbidities because it is more a risk factor for most of these other comorbidities than an individual comorbidity. The results were similar whether or not patients were on antihypertensive medication. We have added a comment on this in the Results (page 10, line 143).

4. The authors need to revise the language especially in the discussion part to improve readability. The specific part that needs revision is found on line 180-181, line 209-210.

Authors’ reply: We have now rephrased these sentences and specifically gone through the Discussion and made some changes to improve readability. We hope you find this acceptable, but we are willing to make any further changes as needed.

Reviewer #2: The authors have described "Primary renal disease modifies the effect of comorbidities on renal replacement therapy patients’ survival". After reading the manuscript thoroughly, i suggest following modifications.

1) Authors include good cohort of RRT patients and studied retrospectively. Can authors kindly explain if its done outpatient setting only or have included patients with continuous renal replacement therapies while in hospital too.

Authors’ reply: Thank you for this clarification. Only patients on chronic kidney replacement therapy and in outpatient setting were included. We have added a sentence on this issue in the Materials and methods (page 4, line 63).

2) Can authors mention if only hemodialysis patients were included / or patients on home therapies were included too as that could change the effect of co morbidities and primary disease on mortality.

Authors’ reply: Also patients on home hemodialysis and peritoneal dialysis were included. We have added this information on other treatment modalities at the initiation of kidney replacement therapy in the Results (page 7, lines 109–110).

3) Table-1 indicates that among pts with polycystic kidney disease, significant number 9.6 % underwent renal transplant as compared to type 2 DM with 3.1%. Can authors elaborate if that has any potential impact on over all mortality .

Authors’ reply: It is true that kidney transplantation is associated with better survival and may well have an impact on overall mortality but the causes (comorbidities and other factors) in patients who did not receive kidney transplant also affect mortality. Survival is better in patients with PKD than in patients with type 2 diabetes, they have fever comorbidities, and they receive more kidney transplants. However, the association between comorbidities and mortality is stronger in patients with PKD than in patients with type 2 diabetes. Therefore, the difference between the number of kidney transplants in these groups should not explain our results. In addition, the criteria for accepting patients on transplantation waitlist are the same regardless of the primary kidney disease.

4) Table-2 indicates that most of the co morbidities including CAD, peripheral vascular disease, left ventricular hypertrophy, more than 3 Co morbidities is highest among Type 2 DM and patients with Nephrosclerosis, which in turn correlate with increased mortality. However in the results sections, authors concluded that Polycystic kidney disease, GN are associated with increase mortality. How do authors explain this variation.

Authors’ reply: As you mentioned, the patients with type 2 diabetes or nephrosclerosis have the highest number of comorbidities and the worst survival. The patients with polycystic kidney disease or glomerulonephritis have better prognosis, but in this study we show that comorbidities have a stronger worsening effect on survival among these patients. Therefore, if patients have multiple comorbidities the difference in survival is smaller between the primary kidney disease groups.

5)Multiple studies mentioned uncontrolled hypertension as independent risk of mortality among ESRD patients on RRT. However the results are the study are opposite. Can authors elaborate on this

Authors’ reply: It is true that treatment of hypertension reduces mortality in patients on dialysis, but also other epidemiological studies than ours have shown reverse association with hypertension and mortality among RRT patients. This may be due to increased mortality associated with hypotension. We have elaborated this issue now in the Discussion and added two references (page 15, lines 234–237).

6) Appears that majority on patients in Finland are white population and hence these results could not be generalized to other parts of world with predominant black / asian population. Would be interesting to see sub group analysis on older age and race if they preset with similar findings.

Authors’ reply: Unfortunately, we do not have the information on race. Even if we would have this information it would be difficult to present reliable results according to race because these subgroups would be too small. Also analyses according to age groups would reduce the number of patients and events too much in some diagnosis groups. For example, there were only 13 patients with type 1 diabetes over the age of 75 and 72 patients with nephrosclerosis under the age of 55. There were similar trends between diagnosis groups and number of comorbidities in different age groups as in our main results, but due to this insufficient number of patients in various subgroups, we do not think these results would be representative of this manuscript, but we can add these as needed.

Submitted filename: Response to Reviewers PLOS ONE.docx

Click here for additional data file.

24 May 2021

PONE-D-20-35936R1

Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients’ survival

PLOS ONE

Dear Dr. Helve,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Maria Lourdes Gonzalez Suarez, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Thank you for submitting this revised version of your manuscript and addressing our reviewers comments. Please address new comments made by our reviewers, specifically review data in supplemental tables, and body of the manuscript were you are mention a higher risk of mortality in patients with PKD and GN when compared to the other subsets., while in the text you state that their survival rate is similar to other patients with multiple comorbidities.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Dr. Helve,

I have reviewed the revised version of your manuscript thoroughly. Thank you for responding to my comments and clarifying the information. I am satisfied with your revisions for the cutoff scores for the obesity and underweight. I am also satisfied with your explanation why hypertension was not included as a comorbidity. It was also helpful that you mentioned that patients with higher blood pressure had lower risk of mortality which further supports the notion that intradialytic hypotension is worse for patients on KRT.

After going over the manuscript and the data, I do have some additional comments. My main take away after reading is that I agree that we must take the primary renal disease into account and not just the comorbidities of the patient when thinking about prognosis. But I think there needs to be more emphasis as to why patients with PKD or GN who have underlying heart failure, malignancy or coronary artery disease are associated with higher mortality rates compared to the other subset of patients.

• The data is clear that patients with PKD or GN have less comorbidities (Table 2) and better survival (Table 1) compared to those with diabetes or nephrosclerosis. But then both the adjusted and unadjusted data show that they have a higher risk of mortality if they have heart failure, malignancy or coronary artery disease. It might be helpful to explain why patients with PKD or GN still have better survival compared to the other subsets despite having a higher risk of mortality when they have specific comorbidities.

• Since patients with PKD or GN had higher rates of kidney transplantation and may have an impact on survival, were you able to see if the results will be affected after adjusting for kidney transplantation? If you think this is not worthwhile to look at, then maybe it will be helpful to provide a brief explanation in the manuscript as to why you think it will not impact the results of your study.

• After looking at the data on Table S3, it appears that patients who have PKD or GN with 3 or more comorbidities have a higher risk of death compared to the other subsets. But then, in the discussion, it mentioned that these patients have similar survival compared to other patients (line 198-199). Is there an explanation for this variation?

Overall, I think this version has better readability. But I think it would be helpful to go over the manuscript again for some minor grammatical revisions.

Reviewer #2: Authors have made significant improvement to raised questions. Can the authors comment in conclusions and elaborate how this study will be useful and have implication in changing the current clinical practice.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

30 Jun 2021

The authors’ detailed response to the Additional Editors and Reviewers comments on the manuscript “Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients’ survival”

Additional Editor Comments:

Thank you for submitting this revised version of your manuscript and addressing our reviewers comments. Please address new comments made by our reviewers, specifically review data in supplemental tables, and body of the manuscript were you are mention a higher risk of mortality in patients with PKD and GN when compared to the other subsets., while in the text you state that their survival rate is similar to other patients with multiple comorbidities.

Authors’ reply:

In the manuscript, we show that the effect of comorbidities on the risk of death is different in different kidney disease diagnoses, and in PKD and GN patients the effect is the strongest. This results in that the survival prognosis of PKD and GN patients with multiple comorbidities is similar to that of patients in other diagnostic groups with multiple comorbidities, although the prognosis is better in PKD and GN patients without comorbidities than in patients with other kidney disease diagnoses without comorbidities. We have worked to improve the manuscript to make this message clearer. Please also see the response to these comments of the Reviewers.

Reviewer #1:

I have reviewed the revised version of your manuscript thoroughly. Thank you for responding to my comments and clarifying the information. I am satisfied with your revisions for the cutoff scores for the obesity and underweight. I am also satisfied with your explanation why hypertension was not included as a comorbidity. It was also helpful that you mentioned that patients with higher blood pressure had lower risk of mortality which further supports the notion that intradialytic hypotension is worse for patients on KRT.

After going over the manuscript and the data, I do have some additional comments. My main take away after reading is that I agree that we must take the primary renal disease into account and not just the comorbidities of the patient when thinking about prognosis. But I think there needs to be more emphasis as to why patients with PKD or GN who have underlying heart failure, malignancy or coronary artery disease are associated with higher mortality rates compared to the other subset of patients.

• The data is clear that patients with PKD or GN have less comorbidities (Table 2) and better survival (Table 1) compared to those with diabetes or nephrosclerosis. But then both the adjusted and unadjusted data show that they have a higher risk of mortality if they have heart failure, malignancy or coronary artery disease. It might be helpful to explain why patients with PKD or GN still have better survival compared to the other subsets despite having a higher risk of mortality when they have specific comorbidities.

Authors’ reply:

Thank you for this comment because this is an essential issue for readers to understand correctly. Patients with PKD or GN without comorbidity have the lowest risk of mortality compared to the patients with other primary kidney disease without comorbidities. When PKD or GN patients have comorbidities the relative risk of death compared to PKD or GN patients without comorbidities increases more than it increases in patients with other kidney diseases when assessing the effect of comorbidities on mortality in that diagnosis group. This results a bigger difference between the survival probability of PKD or GN patients with and without comorbidities than in other primary kidney disease groups. Therefore, the survival is similar in all diagnosis groups when patients with multiple comorbidities are compared. We have clarified this issue in the Results, page 9, line 130, and page 12, line 170, and in the Discussion, page 12, lines 180 and 186.

• Since patients with PKD or GN had higher rates of kidney transplantation and may have an impact on survival, were you able to see if the results will be affected after adjusting for kidney transplantation? If you think this is not worthwhile to look at, then maybe it will be helpful to provide a brief explanation in the manuscript as to why you think it will not impact the results of your study.

Authors’ reply:

It is likely that kidney transplantation has an effect on survival and patients with PKD or GN had more often transplantation. Therefore, we made a sensitivity analysis where patients were censored at kidney transplantation and the results were similar. This is mentioned in page 11, line 154. We think that this is a better way to take an impact of kidney transplantation into account than adjustment for kidney transplantation, because in that case we would adjust the estimate of patients survival probability at the start of kidney replacement therapy with a future event (transplantation). However, we analysed how number of comorbidities associated with risk of death and multivariable model on comorbidities’ association with the risk of death with adjustment also for kidney transplantation and the results were similar, but due to the reasons mentioned above we did not add this information in the manuscript.

• After looking at the data on Table S3, it appears that patients who have PKD or GN with 3 or more comorbidities have a higher risk of death compared to the other subsets. But then, in the discussion, it mentioned that these patients have similar survival compared to other patients (line 198-199). Is there an explanation for this variation?

Authors’ reply:

Table S3 compares the relative risk of death according to number of comorbidities within that one kidney diagnosis group. PKD patients without comorbidity have median survival time over 18 years which is higher than in other diagnosis groups, but the relative risk of death associated with number of comorbidities is greater than in PKD patients than in other diagnosis groups and therefore in PKD patients with multiple comorbidities the median survival time decreases to the same level with other patients with multiple comorbidities. We have clarified this in the manuscript, page 12, lines 170 and 186.

Overall, I think this version has better readability. But I think it would be helpful to go over the manuscript again for some minor grammatical revisions.

Authors’ reply:

The manuscript has now been revised and amended in line with the recommendations of the professional language examiner. We hope the text is clearer now.

Reviewer #2:

Authors have made significant improvement to raised questions. Can the authors comment in conclusions and elaborate how this study will be useful and have implication in changing the current clinical practice.

Authors’ reply:

Thank you for this comment. Many prognostic models have been made to assess the survival of patients starting kidney replacement therapy. However, these models do not take into account the difference in impact of comorbidities on survival in different kidney diagnoses. If you use these models in clinical practice, it may lead to a wrong assessment in some patients and could have an influence on the decision how patient is treated. We have added a sentence on this in the Discussion, page 15, line 247.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

10 Aug 2021

Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients’ survival

PONE-D-20-35936R2

Dear Dr. Helve,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Maria Lourdes Gonzalez Suarez, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Jaako Helve and co-authors,

Thank you for addressing our comments and sending this revised version of your manuscript. We believe it has clarified all concerns and it has made it easier to read.

Best regards,

Maria L. Gonzalez Suarez, MD, PhD

13 Aug 2021

PONE-D-20-35936R2

Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients’ survival

Dear Dr. Helve:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Maria Lourdes Gonzalez Suarez

Academic Editor

PLOS ONE