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• Published: 10 January 2022

Chronic kidney disease and its health-related factors: a case-control study

• Mousa Ghelichi-Ghojogh 1 ,
• Mohammad Fararouei 2 ,
• Mozhgan Seif 3 &
• Maryam Pakfetrat 4  

BMC Nephrology volume  23 , Article number:  24 ( 2022 ) Cite this article

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Chronic kidney disease (CKD) is a non-communicable disease that includes a range of different physiological disorders that are associated with abnormal renal function and progressive decline in glomerular filtration rate (GFR). This study aimed to investigate the associations of several behavioral and health-related factors with CKD in Iranian patients.

A hospital-based case-control study was conducted on 700 participants (350 cases and 350 controls). Logistic regression was applied to measure the association between the selected factors and CKD.

The mean age of cases and controls were 59.6 ± 12.4 and 58.9 ± 12.2 respectively ( p  = 0.827). The results of multiple logistic regression suggested that many factors including low birth weight (OR yes/no  = 4.07, 95%CI: 1.76–9.37, P  = 0.001), history of diabetes (OR yes/no  = 3.57, 95%CI: 2.36–5.40, P  = 0.001), history of kidney diseases (OR yes/no  = 3.35, 95%CI: 2.21–5.00, P  = 0.001) and history of chemotherapy (OR yes/no  = 2.18, 95%CI: 1.12–4.23, P  = 0.02) are associated with the risk of CKD.

Conclusions

The present study covered a large number of potential risk/ preventive factors altogether. The results highlighted the importance of collaborative monitoring of kidney function among patients with the above conditions.

Peer Review reports

Chronic kidney disease (CKD) is a non-communicable disease that includes a range of different physiological disorders that are associated with an abnormal renal function and progressive decline in glomerular filtration rate (GFR) [ 1 , 2 , 3 ]. Chronic kidney disease includes five stages of kidney damage, from mild kidney dysfunction to complete failure [ 4 ]. Generally, a person with stage 3 or 4 of CKD is considered as having moderate to severe kidney damage. Stage 3 is broken up into two levels of kidney damage: 3A) a level of GFR between 45 to 59 ml/min/1.73 m 2 , and 3B) a level of GFR between 30 and 44 ml/min/1.73 m 2 . In addition, GFR for stage 4 is 15–29 ml/min/1.73 m 2 [ 4 , 5 ]. It is reported that both the prevalence and burden of CKD are increasing worldwide, especially in developing countries [ 6 ]. The worldwide prevalence of CKD (all stages) is estimated to be between 8 to 16%, a figure that may indicate millions of deaths annually [ 7 ]. According to a meta-analysis, the prevalence of stage 3 to 5 CKD in South Africa, Senegal, and Congo is about 7.6%. In China, Taiwan, and Mongolia the rate of CKD is about 10.06% and in Japan, South Korea, and Oceania the rate is about 11.73%. In Europe the prevalence of CKD is about 11.86% [ 8 ], and finally, about 14.44% in the United States and Canada. The prevalence of CKD is estimated to be about 11.68% among the Iranian adult population and about 2.9% of Iranian women and 1.3% of Iranian men are expected to develop CKD annually [ 9 ]. Patients with stages 3 or 4 CKD are at much higher risk of progressing to either end-stage renal disease (ESRD) or death even prior to the development of ESRD [ 10 , 11 ].

In general, a large number of risk factors including age, sex, family history of kidney disease, primary kidney disease, urinary tract infections, cardiovascular disease, diabetes mellitus, and nephrotoxins (non-steroidal anti-inflammatory drugs, antibiotics) are known as predisposing and initiating factors of CKD [ 12 , 13 , 14 ]. However, the existing studies are suffering from a small sample size of individuals with kidney disease, particularly those with ESRD [ 15 ].

Despite the fact that the prevalence of CKD in the world, including Iran, is increasing, the factors associated with CKD are explored very little. The present case-control study aimed to investigate the association of several behavioral and health-related factors with CKD in the Iranian population.

Materials and methods

In this study, participants were selected among individuals who were registered or were visiting Faghihi and Motahari hospitals (two largest referral centers in the South of Iran located in Shiraz (the capital of Fars province). Cases and controls were frequency-matched by sex and age. The GFR values were calculated using the CKD-EPI formula [ 16 , 17 ].

Data collection

An interview-administered questionnaire and the participant’s medical records were used to obtain the required data. The questionnaire and interview procedure were designed, evaluated, and revised by three experts via conducting a pilot study including 50 cases and 50 controls. The reliability of the questionnaire was measured using the test-retest method (Cronbach’s alpha was 0.75). The interview was conducted by a trained public health‌ nurse at the time of visiting the clinics.

Avoiding concurrent conditions that their association may interpreted as reverse causation; the questionnaire was designed to define factors preceding at least a year before experiencing CKD first symptoms. Accordingly participants reported their social and demographic characteristics (age, sex, marital status, educational level, place of residency), history of chronic diseases (diabetes, cardiovascular diseases, hypertension, kidney diseases, family history of kidney diseases, autoimmune diseases and thyroid diseases [ 18 ]). Also history of other conditions namely (smoking, urinary tract infection (UTI), surgery due to illness or accident, low birth weight, burns, kidney pain (flank pain), chemotherapy, taking drugs for weight loss or obesity, taking non-steroidal anti-inflammatory drugs, and taking antibiotic) before their current condition was started. Many researchers reported recalling birth weight to be reliable for research purposes [ 19 ]. Moreover, we asked the participants to report their birth weight as a categorical variable (< 2500 g or low, 2500- < 3500 g or normal, and > 3500 g or overweight). Medical records of the participants were used to confirm/complete the reported data. In the case of contradiction between the self-reported and recorded data, we used the recorded information for our study.

Verbal informed consent was obtained from patients because the majority of the participants were illiterate. The study protocol was reviewed and approved by the ethical committee of Shiraz University of Medical Sciences (approval number: 1399.865).

Sample size

The sample size was calculated to detect an association‌ between the history of using antibiotics (one of our main study variables) and CKD as small as OR = 1.5 [ 20 ]. With an alpha value of 0.05 (2-sided) and a power of 80%, the required sample size was estimated as large as n  = 312 participants for each group.

Selection of cases

The selected clinics deliver medical care to patients from the southern part of the country. In this study, patients with CKD who were registered with the above centers from June to December 2020 were studied. A case was a patient with a GFR < 60 (ml/min/1.73 m 2 ) at least twice in 3 months. According to the latest version of the International Classification of Diseases (2010), Codes N18.3 and N18.4 are assigned to patients who have (GFR = 30–59 (ml/min/1.73 m 2 ) and GFR = 15–29 (ml/min/1.73 m 2 ) respectively [ 21 ]. In total, 350 patients who were diagnosed with CKD by a nephrologist during the study period.

Selection of the controls

We used hospital controls to avoid recall-bias. The control participants were selected from patients who were admitted to the general surgery (due to hernia, appendicitis, intestinal obstruction, hemorrhoids, and varicose veins), and orthopedic wards‌ from June to December 2020. Using the level of creatinine in the participants’ serum samples, GFR was calculated and the individuals with normal GFR (ml/min/1.73 m 2 ) GFR > 60) and those who reported no history of CKD were included ( n  = 350).

Inclusion criteria

Patients were included if they were ≥ 20 years old and had a definitive diagnosis of CKD by a nephrologist.

Exclusion criteria

Participants were excluded if they were critically ill, had acute kidney injury, those undergone renal transplantation, and those with cognitive impairment.

Statistical analysis

The Chi-square test was used to measure the unadjusted associations between categorical variables and CKD. Multiple logistic regression was applied to measure the adjusted associations for the study variables and CKD. The backward variable selection strategy was used to include variables in the regression model. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. All p -values were two-sided and the results were considered statistically significant at p  < 0.05. All analyses were conducted using Stata version 14.0 (Stata Corporation, College Station, TX, USA).

In total, 350 cases and 350 age and sex-matched controls were included in the analysis. The mean age of cases and controls were 59.6 ± 12.4 and 58.9 ± 12.2 respectively ( p  = 0.83). Overall, 208 patients (59.4%) and 200 controls (57.1%) were male ( p  = 0.54). Also, 149 patients (42.6%) and 133 controls (38.0%) were illiterate or had elementary education ( p  = 0.001). Most cases (96.9%) and controls (95.7%) were married ( p  = 0.42). The mean GFR for CKD and control groups were 38.6 ± 11.4 and 78.3 ± 10.2 (ml/min/1.73 m2) respectively.

Result of univariate analysis

Table  1 illustrates the unadjusted associations of demographic and health-related variables with CKD. Accordingly, significant (unadjusted) associations were found between the risk of CKD and several study variables including education, history of chronic diseases (diabetes, cardiovascular, hypertension, kidney diseases, autoimmune diseases, and hypothyroidism), family history of kidney diseases, smoking, UTI, surgery due to illness or accident, low birth weight, burns, kidney pain, chemotherapy, taking non-steroidal anti-inflammatory drugs, and taking antibiotics) ( P  < 0.05 for all).

Results of multivariable analysis

Table  2 illustrates the adjusted associations between the study variables and the risk of CKD. Most noticeably, low birth weight (OR yes/no  = 4.07, 95%CI: 1.76–9.37, P  = 0.001), history of surgery (OR yes/no  = 1.74, 95%CI: 1.18–2.54, P  = 0.004), family history of kidney diseases (OR yes/no  = 1.97, 95%CI: 1.20–3.23, P  = 0.007), and history of chemotherapy (OR yes/no  = 2.18, 95%CI: 1.12–4.23, P  = 0.02) were significantly associated with a higher risk of CKD. On the other hand, education (OR college/illiterate or primary  = 0.54, 95%CI: 0.31–0.92, P  = 0.025) was found to be inversely associated with CKD.

The results of the present study suggested that several variables including, education, history of diabetes, history of hypertension, history of kidney diseases or a family history of kidney diseases, history of surgery due to illness or accident, low birth weight, history of chemotherapy, history of taking non-steroidal anti-inflammatory drugs, and history of taking antibiotics may affect the risk of CKD.

In our study, the level of education was inversely associated with the risk of CKD. This finding is in accordance with the results of a study conducted by K Lambert et.al, who suggested that illiteracy or elementary education may raise the risk of CKD [ 22 ]. The fact that education level is associated with health literacy, may partly explain our results that lower education and inadequate health literacy in individuals with CKD is associated with worse health outcomes including poorer control of biochemical parameters, higher risk of cardiovascular diseases (CVDs); a higher rate of hospitalization, and a higher rate of infections [ 23 ].

In the current study, the history of diabetes was associated with a higher risk of CKD. This finding is consistent with the results of other studies on the same subject [ 20 , 21 , 24 , 25 , 26 , 27 ]. It is not surprising that people with diabetes have an increased risk of CKD as diabetes is an important detrimental factor for kidney functioning as approximately, 40% of patients with diabetes develop CKD [ 27 ].

The other variable that was associated with an increased risk of CKD was a history of hypertension. Our result is consistent with the results of several other studies [ 20 , 24 , 25 , 28 ]. It is reported that hypertension is both a cause and effect of CKD and accelerates the progression of the CKD to ESRD [ 29 ].

After controlling for other variables, a significant association was observed between family history of kidney diseases and risk of CKD. Published studies suggested the same pattern [ 24 ]. Inherited kidney diseases (IKDs) are considered as the foremost reasons for the initiation of CKD and are accounted for about 10–15% of kidney replacement therapies (KRT) in adults [ 30 ].

The importance of the history of surgery due to illness or accident in this study is rarely investigated by other researchers who reported the effect of surgery in patients with acute kidney injury (AKI), and major abdominal and cardiac surgeries [ 31 , 32 ] on the risk of CKD. Also, AKI is associated with an increased risk of CKD with progression in various clinical settings [ 33 , 34 , 35 ]. In a study by Mizota et.al, although most AKI cases recovered completely within 7 days after major abdominal surgery, they were at higher risk of 1-year mortality and chronic kidney disease compared to those without AKI [ 31 ].

The present study also showed that low birth weight is a significant risk factor for CKD. This finding is consistent with the results of some other studies. However, the results of very few studies on the association between birth weight and risk of CKD are controversial as some suggested a significant association [ 19 , 36 , 37 ] whereas others suggested otherwise [ 36 ]. This may be explained by the relatively smaller size and volume of kidneys in LBW infants compared to infants that are normally grown [ 38 ]. This can lead to long-term complications in adolescence and adulthood including hypertension, decreased glomerular filtration, albuminuria, and cardiovascular diseases. Eventually, these long-term complications can also cause CKD [ 39 ].

Another important result of the current study is the association between chemotherapy for treating cancers and the risk of CKD. According to a study on chemotherapy for testicular cancer by Inai et al., 1 year after chemotherapy 23% of the patients showed CKD [ 40 ]. Another study suggested that the prevalence of stage 3 CKD among patients with cancer was 12, and < 1% of patients had stage 4 CKD [ 41 , 42 ]. Other studies have shown an even higher prevalence of CKD among cancer patients. For instance, only 38.6% of patients with breast cancer, 38.9% of patients with lung cancer, 38.3% of patients with prostate cancer, 27.5% of patients with gynecologic cancer, and 27.2% of patients with colorectal cancer had a GFR ≥90 (ml/min/1.73 m 2 ) at the time of therapy initiation [ 43 , 44 ]. The overall prevalence of CKD ranges from 12 to 25% across many cancer patients [ 45 , 46 , 47 ]. These results clearly demonstrate that, when patients with cancer develop acute or chronic kidney disease, outcomes are inferior, and the promise of curative therapeutic regimens is lessened.

In our study, the history of taking nephrotoxic agents (antibiotics or NSAIDs drugs) was associated with a higher risk of CKD. Our result is following the results reported by other studies [ 48 , 49 ]. Common agents that are associated with AKI include NSAIDs are different drugs including antibiotics, iodinated contrast media, and chemotherapeutic drugs [ 50 ].

Strengths and limitations of our study

Our study used a reasonably large sample size. In addition, a considerably large number of study variables was included in the study. With a very high participation rate, trained nurses conducted the interviews with the case and control participants in the same setting. However, histories of exposures are prone to recall error (bias), a common issue in the case-control studies. It is to be mentioned that the method of selecting controls (hospital controls) should have reduced the risk of recall bias when reporting the required information. In addition, we used the participants’ medical records to complete/ confirm the reported data. Although the design of the present study was not able to confirm a causal association between the associated variables and CKD, the potential importance and modifiable nature of the associated factors makes the results potentially valuable and easily applicable in the prevention of CKD.

Given that, chemotherapy is an important risk factor for CKD, we suggest the imperative for collaborative care between oncologists and nephrologists in the early diagnosis and treatment of kidney diseases in patients with cancer. Training clinicians and patients are important to reduce the risk of nephrotoxicity. Electronic medical records can simultaneously be used to monitor prescription practices, responsiveness to alerts and prompts, the incidence of CKD, and detecting barriers to the effective implementation of preventive measures [ 51 ]. Routine follow-up and management of diabetic patients is also important for the prevention of CKD. We suggest a tight collaboration between endocrinologists and nephrologists to take care of diabetic patients with kidney problems. In addition, surgeons in major operations should refer patients, especially patients with AKI, to a nephrologist for proper care related to their kidney function. Treatment of hypertension is among the most important interventions to slow down the progression of CKD [ 12 ]. Moreover, all patients with newly diagnosed hypertension should be screened for CKD. We suggest all patients with diabetes have their GFR and urine albumin-to-creatinine ratio (UACR) checked annually. Finally, the aging population and obesity cause the absolute numbers of people with diabetes and kidney diseases to raise significantly. This will require a more integrated approach between dialectologists/nephrologists and the primary care teams (55).

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to their being the intellectual property of Shiraz University of Medical Sciences but are available from the corresponding author on reasonable request.

Abbreviations

• Chronic kidney disease

End-stage renal disease

Glomerular filtration rate

Renal replacement treatment

Urinary tract infection

Odds ratios

Confidence intervals

Hypertension

Acute kidney injury

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Acknowledgments

This paper is part of a thesis conducted by Mousa Ghelichi-Ghojogh, Ph.D. student of epidemiology, and a research project conducted at the Shiraz University of Medical sciences (99-01-04-22719). We would like to thank Dr. Bahram Shahryari and all nephrologists of Shiraz‌ University of medical sciences, interviewers, and CKD patients in Shiraz for their voluntary participation in the study and for providing data for the study.

Shiraz University of Medical Sciences financially supported this study. (Grant number: 99–01–04-22719).

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Candidate in Epidemiology, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

Mousa Ghelichi-Ghojogh

HIV/AIDS research center, School of Health, Shiraz University of Medical Sciences, P.O.Box: 71645-111, Shiraz, Iran

Mohammad Fararouei

Department of Epidemiology, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran

Mozhgan Seif

Nephrologist, Shiraz Nephro-Urology Research Center, Department of Internal Medicine, Emergency Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Maryam Pakfetrat

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Contributions

MGG: Conceptualization, Methodology, Statistical analysis, Investigation, and writing the draft of the manuscript. MP: were involved in methodology, writing the draft of the manuscript, and clinical consultation. MS: was involved in the methodology and statistical analysis. MF: was involved in conceptualization, methodology, supervision, writing, and reviewing the manuscript. The authors read and approved the final manuscript.

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Correspondence to Mohammad Fararouei .

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The study protocol was reviewed and approved by the ethical committee of Shiraz University of Medical Sciences (approval number: 1399.865). All methods were performed in accordance with the relevant guidelines and regulations of the Declaration of Helsinki. The participants were assured that their information is used for research purposes only. Because of the illiteracy of a considerable number of the patients, verbal informed consent was obtained from the participants. Using verbal informed consent was also granted by the ethical committee of Shiraz University of Medical Sciences.

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Ghelichi-Ghojogh, M., Fararouei, M., Seif, M. et al. Chronic kidney disease and its health-related factors: a case-control study. BMC Nephrol 23 , 24 (2022). https://doi.org/10.1186/s12882-021-02655-w

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A 60-year-old man with chronic renal failure and a costal mass: a case report and review of the literature

• Germán Campuzano-Zuluaga 1 ,
• William Velasco-Pérez 1 &
• Juan Ignacio Marín-Zuluaga 1  

Journal of Medical Case Reports volume  3 , Article number:  7285 ( 2009 ) Cite this article

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Introduction

Brown tumors are a rare focal manifestation of osteitis fibrosa cystica, which results from hyperparathyroidism. Chronic kidney failure may lead to secondary or tertiary hyperparathyroidism and thus to osteitis fibrosa cystica and brown tumors.

Case presentation

A 60-year-old man with a history of diabetes mellitus and chronic kidney failure presented with a 15-day history of dyspnea, cough, malaise and fever. Initially, there was little correlation between his history and his physical examination. Various pulmonary, cardiac and infectious etiologies were ruled out. A chest X-ray showed a costal mass that was further verified by tomography and gammagraphy. The mass was suspected of being neoplastic. After a failed biopsy, the mass was removed surgically and on histopathology was compatible with a giant-cell tumor versus a brown tumor caused by hyperparathyroidism. Laboratory tests showed elevated calcium, phosphate and parathyroid hormone concentrations. The patient was diagnosed with a brown tumor secondary to refractory hyperparathyroidism.

Tending towards a diagnosis because it is more frequent or it implies more risk for the patient may delay the consideration of other diagnostic options that, although rare, fit well into the clinical context. The patient presented here was suspected to have an osseous neoplasia that would have had major implications for the patient. However, reassessment of the case led to the diagnosis of a brown tumor. Brown tumors should be an important diagnostic consideration in patients with chronic kidney failure who have secondary or tertiary hyperparathyroidism and an osseous mass.

The first case in the literature reporting a brown tumor was published in 1953 and described a fronto-ethmoidal brown tumor [ 1 ]. However, previous reports of patients with localized forms of osteitis fibrosa cystica (OFC) suggest that the clinical entity was described earlier, at a time when there were few treatment options for chronic kidney failure (CKF) and consequently chronic hyperparathyroidism was more prevalent. Brown tumors are rare osseous lesions that represent a focal manifestation of OFC resulting from hyperparathyroid states. Patients suffering from CKF may develop secondary or tertiary hyperparathyroidism due to altered phosphorus and calcium metabolism. Persistent hyperparathyroidism leads to altered osseous metabolism with bone resorption and tissue changes collectively known as OFC. Our case report describes a patient with poorly controlled CKF who presented with a non-specific clinical picture and no clear diagnosis. Incidentally a costal mass was found and the diagnostic workup that followed led to an unexpected diagnosis.

A 60-year-old man was transferred from the hemodialysis unit to the emergency room because of a 15-day history of malaise, subjective fever, shortness of breath, dry cough, abdominal pain and diarrhea. He also complained of mild anterior thoracic pain not associated with other symptoms and which was not irradiated. He had a 20-year history of type 2 diabetes mellitus (DM) that required insulin, with micro- and macro-vascular complications such as diabetic retinopathy and CKF. He was on hemodialysis and had a history of multiple failed dialysis accesses. He also suffered from arterial hypertension, upper and lower extremity peripheral arterial disease, carotid artery disease, a first degree atrioventricular heart block and had smoked one packet of cigarettes per day for the last 20 years. He was being treated with sevelamer, erythropoietin, folic acid, lovastatin, gemfibrozil, NPH insulin, amlodipine and acetylsalicylic acid, but was not receiving calcium or a vitamin D supplement.

A physical examination revealed the patient to be in a fair condition, with no apparent distress, hydrated, alert and well oriented. He had a heart rate of 92 beats per minute, respiratory rate of 14 breaths per minute, blood oxygen saturation of 97%, arterial blood pressure of 130/70 mmHg and no fever. He had bilateral blindness and mild epistaxis through the left nostril. The thorax was tender to palpation in some costochondral unions, but pain was poorly localized. The vesicular murmur had reduced intensity and no pathologic sounds were auscultated. Peripheral pulses were weak in both the upper and the lower limbs. He had a translumbar hemodialysis catheter. The remaining physical examination was unremarkable.

The patient had stable vital signs and had no signs of systemic inflammatory response. However, because of the patient's previous history of DM, CKF and the presence of leukocytosis, neutrophilia and elevated C-reactive protein upon admission (Table 1 ), we initially ruled out a gastrointestinal or lung infection, or any cardiac cause for the patient's symptoms. The electrocardiogram showed no signs of ischemia, and the chest X-ray showed cardiomegaly, a small left pleural effusion, a circular opacity in the right inferior thoracic region and no signs of consolidation. These findings were initially interpreted as a pulmonary infection, probably a lung abscess, an abscedated nodule or pulmonary tuberculosis. A contrast tomography scan of the chest was ordered for further characterization. Though it showed no parenchymal compromise, a 4 × 1.3 cm lesion was observed on the right dorsal region of the eighth rib. The lesion showed thinning of cortical bone in some areas, preserved cortex and lacked periosteal reaction (Figure 1 ). The radiology staff considered a bone metastasis as a first diagnostic option, and a thoraco-abdomino-pelvic tomography scan was done in search for more lesions and a probable primary tumor. Additional hypodense lesions were observed, including one on the left lamina of L4, acetabulum, and head and neck of the right femur. There was no lymph-node or internal organ compromise. A Tc 99 m Medronate osseous gammagraphy reported a hypermetabolic focus compatible with a neoplastic lesion, concordant in size and location with the costal mass reported in the previous imaging studies. It also revealed generalized osseous compromise compatible with renal osteodystrophy and did not confirm the other lesions described on tomography. A tomography-guided biopsy specimen (Figure 1 ) was obtained, but histopathological analysis reported normal tissue components.

Tomographic image during guided biopsy procedure . Note the heterogeneous 4 × 1.3 cm mass (arrow), with preserved cortical bone and no periosteal reaction or other inflammatory signs. No cysts were identified.

Not being able to reach a clear diagnosis, a careful reassessment of the patient's clinical record led to considering the alternative diagnosis of renal osteodystrophy. This was supported by a history of poorly controlled CKF, elevated calcium (11.2 mg/dl) and phosphorus (5.3 mg/dl) concentrations, a phosphocalcic product of 59.36 mg 2 /dl 2 , and a bone gammagraphy that showed changes compatible with OFC. However, the possibility of neoplasia was still being considered so the mass was removed surgically. Histopathological studies reported an osseous tissue with spindles of fusiform cells in a storiform disposition with abundant multinucleated giant cells, some macrophages and some mononuclear cells. Scarce mitotic activity was observed, and there were no signs of malignancy (Figure 2 ). The pathologist concluded that the findings were compatible with a giant-cell tumor or a brown tumor, both histologically very similar [ 2 ]. Parathyroid hormone (PTH) concentration was 1377 pg/ml. These findings were compatible with refractory hyperparathyroidism, and a diagnosis of a brown tumor of hyperparathyroidism associated with CKF was reached.

Microscopic pathology of surgical specimen . Presence of various multinucleated giant cells (arrows) and spindle arranged cells. Hemosiderin deposits were not observed in the sample. Hematoxylin-eosin stain at 40 × magnification.

The patient continued ambulatory medical treatment with vitamin D, calcium and sevelamer. Two months after discharge, the parathyroid level was 1900 pg/ml and a Tc 99 m Sestamibi scan revealed hyperfunctioning glands despite aggressive pharmacological treatment. Serum calcium and phosphorus levels were within normal limits, 9.4 mg/dl and 3.4 mg/dl, respectively. At the time of writing, the patient was awaiting parathyroidectomy as definite treatment for tertiary hyperparathyroidism associated with severe renal osteodystrophy.

Brown tumors are unusual bone lesions that represent a localized manifestation of OFC induced by hyperparathyroidism, independent of its cause. Increased PTH levels and locally produced tumour necrosis factor α and interleukin 1 (IL-1) by marrow monocytes induce the proliferation and differentiation of pluripotent bone-marrow cells into osteoblasts. These cells produce granulocyte macrophage colony stimulating factor, IL-6, IL-11 and stem-cell factor that induce the migration and differentiation of monocytes into osteoclasts, increasing the number of the latter in the bone tissue. Enhanced activity of osteoclasts and osteoblasts leads to bone resorption and a reduction of bone mineral concentration with an increased proliferation of fibrous tissue and extracellular matrix [ 3 ]. Brown tumors develop in 3% to 4% of patients with primary hyperparathyroidism and in 1.5% to 1.7% of patients with secondary causes of hyperparathyroidism [ 4 ]. However, around half of patients with CKF may develop OFC due to secondary hyperparathyroidism making brown tumors more frequent in these patients. Brown tumors have been reported in patients with primary hyperparathyroidism due to adenomas [ 5 ] and carcinomas [ 6 ] of the parathyroid gland; vitamin D deficiency due to lack of sunlight exposure [ 7 ] or due to intestinal malabsorption syndromes [ 8 ]; and secondary [ 9 ] or tertiary hyperthyroidism [ 10 ] in patients suffering CKF. Hyperphosphatemia with hypocalcemia caused by tubular damage and impaired vitamin D metabolism explains hyperparathyroidism in these patients.

Brown tumors are either mono- or polyostotic benign masses, painless and usually found incidentally. However, they may cause tissue damage to adjacent structures and compressive manifestations such as pain, neuropathies [ 11 ] and myelopathy [ 12 ]. The majority of cases report the maxilla and mandible as the main sites of occurrence [ 9 ]. Other common sites are the clavicles, scapula, pelvis and ribs; however, these lesions may appear in any osseous structure [ 7 ], including chondral tissue [ 13 ]. They are associated with an increased risk of fractures if localized in weight-bearing areas [ 14 ].

Brown tumors arise from foci of OFC and represent a reparative bone process rather than true neoplastic lesions, as there is no hyperplasia or clonal cell proliferation. Typical histopathology describes spindle cells or fibroblasts in areas of osseous lysis, multinucleated giant cells (probably osteoclasts), increased vascularization and accumulation of hemosiderin-laden macrophages, with micro-hemorrhages which confer a brownish appearance to the affected tissue. Cysts and areas of necrosis may be found [ 2 , 5 ]. Brown tumors are histologically similar to giant-cell tumors, giant-cell regenerative granulomas, cherubism and aneurismatic osseous cysts [ 2 , 4 ].

On X-ray imaging, brown tumors appear as lytic lesions with thinned cortical bone that may be fractured. Concurrent changes that suggest OFC such as osteopenia, a "salt-and-pepper" bone appearance, subperiosteal bone resorption and disappearance of the lamina dura around the roots of the teeth, may help differentiate it from other entities [ 4 ]. Tomographic imaging shows an osseous mass, with no cortical disruption, no periosteal reaction or inflammatory signs, a heterogeneous center and areas that suggest cysts [ 14 ]. Magnetic resonance imaging (MRI) shows variable intensities on T2-weighted images and intense enhancement on T1-weighted contrast MRI. MRI may be better for determining the presence of cysts or fluid filled levels; a finding that is very suggestive of a brown tumor [ 14 ]. Osseous gammagraphy is not indicated for the diagnosis of brown tumors; however, isolated hypermetabolic lesions or simultaneous hypercaptation of bone lesions and parathyroid adenomas, when done with Tc 99 m Sestamibi, have been described [ 15 ].

Although differential diagnoses for an isolated bone lesion are extensive, when confronted with a patient with CKF, an osseous mass and laboratory data that show increased levels of calcium, phosphate, phosphocalcic product as well as alkaline phosphatase, it is imperative to determine PTH levels to rule out hyperparathyroidism. Histopathological analysis of the osseous lesion is needed to confirm the diagnosis of a brown tumor. In the case presented here, parathyroid levels were not assessed earlier because another diagnosis, osseous neoplasia, was suspected which posed major prognostic value and risk for the patient. A parathyroid hormone measurement six months earlier reported 570 pg/ml; thus, it is probable that the pathological process evolved during this brief time.

Treatment of brown tumors relies on a definitive control of the underlying hyperparathyroid state. In a patient with CKF, this is achieved through the administration of phosphorus chelators, and calcium and vitamin D supplementation. In patients presenting with tertiary hyperparathyroidism, parathyroidectomy may be required. Osseous lesions usually cease to grow, then shrink and eventually ossify without further consequences for the patient. Surgery is required under certain circumstances, such as: 1) compressive neurologic symptoms over peripheral nerves, cauda equina or spinal medulla; 2) a significant anatomical deformity; 3) risk of a pathologic fracture; 4) when the symptoms or pain do not resolve despite adequate medical treatment and control of the hyperparathyroid state; and 5) when the biopsy does not yield a clear diagnosis, as with the present case [ 9 , 11 , 12 ].

The case presented here illustrates how brown tumors, though rare, should be considered in patients with CKF and an osseous mass. The initial clinical presentation of this patient, a history of DM with a non-compensated CKF and the laboratory studies suggested an infectious process. Retrospectively, these initial complaints and findings could be explained by the patient's renal condition with volume overload, severe anemia, hydro-electrolyte disturbances, as well as altered calcium and phosphate metabolism. Early diagnosis and proper management of CKF enable an optimal control of bone-mineral metabolism, thus decreasing the incidence of OFC and making brown tumors rare lesions. Nevertheless, when confronted with a patient with CKF and an osseous mass, a brown tumor caused by hyperparathyroidism should always be considered in the differential diagnosis.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Abbreviations

chronic kidney failure

diabetes mellitus

interleukin 1

interleukin 6

interleukin 11

magnetic resonance imaging

osteitis fibrosa cystica

parathyroid hormone.

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Acknowledgements

We thank the following persons: the patient and his family for the information provided and their approval for the publication of this case; the medical staff at the Hospital Pablo Tobón Uribe, especially the Internal Medicine, Radiology, Surgery and Pathology Departments, and the Nephrology and Dialysis Unit; Dr. Victoria Eugenia Murillo for histopathological analysis, case discussion and photomicrography; Dr. John M. Lopera, Dr. Jorge H. Donado and Ana Isabel Toro for manuscript revision and editing.

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GCZ summarized and interpreted the patient's medical record and was part of the medical staff, did the literature review and wrote the manuscript. WV and JIMZ helped to interpret the patient's medical record, were part of the medical staff and helped to write and review the manuscript. JIMZ was the principal attending physician and responsible for most medical decisions and interpretations expressed in the article. All authors read and approved the final manuscript.

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Campuzano-Zuluaga, G., Velasco-Pérez, W. & Marín-Zuluaga, J.I. A 60-year-old man with chronic renal failure and a costal mass: a case report and review of the literature. J Med Case Reports 3 , 7285 (2009). https://doi.org/10.4076/1752-1947-3-7285

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Article Contents

Introduction, materials and methods, acknowledgements, authors’ contributions, data availability statement, conflict of interest statement.

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Cardiovascular, renal and mortality risk by the KDIGO heatmap in Japan

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Shoichi Maruyama, Tetsuhiro Tanaka, Hiroki Akiyama, Mitsuru Hoshino, Shoichiro Inokuchi, Shuji Kaneko, Koji Shimamoto, Asuka Ozaki, Cardiovascular, renal and mortality risk by the KDIGO heatmap in Japan, Clinical Kidney Journal , Volume 17, Issue 8, August 2024, sfae228, https://doi.org/10.1093/ckj/sfae228

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This study aimed to assess the prognosis of people with chronic kidney disease (CKD) in Japan using the Kidney Disease: Improving Global Outcomes (KDIGO) heatmap.

The prognoses of individuals with estimated glomerular filtration rates (eGFR) <90 mL/min/1.73 m 2 were evaluated based on the KDIGO heatmap using an electronic medical record database in Japan. The primary outcome was major adverse cardiovascular events (MACE), a composite of myocardial infarction (MI), stroke, heart failure (HF) hospitalization and in-hospital death (referred to as MACE1). Additionally, ad hoc MACE2 (MI hospitalization, stroke hospitalization, HF hospitalization and in-hospital death) was examined. The secondary outcome was the renal outcome.

Of the 543 606 individuals included, the mean age was 61.6 ± 15.3 years, 50.1% were male and 40.9% lacked urine protein results. The risk of MACEs increased independently with both eGFR decline and increasing proteinuria from the early KDIGO stages: hazard ratios (95% confidence interval) of MACE1 and MACE2, compared with G2A1 were 1.16 (1.12–1.20) and 1.17 (1.11–1.23), respectively, for G3aA1, and 1.17 (1.12–1.21) and 1.35 (1.28–1.43), respectively, for G2A2. This increased up to 2.83 (2.54–3.15) and 3.43 (3.00–3.93), respectively, for G5A3. Risks of renal outcomes also increased with CKD progression.

This study is the first to demonstrate the applicability of the KDIGO heatmap in assessing cardiovascular and renal risk in Japan. The risk increased from the early stages of CKD, indicating the importance of early diagnosis and intervention through appropriate testing.

What was known:

The Kidney Disease: Improving Global Outcomes (KDIGO) classification was originally developed based on the risk of death, end-stage renal disease and cardiovascular death in people with chronic kidney disease (CKD).

Despite the fact that people with CKD are at high risk for developing cardiovascular diseases, it is unclear whether the risk can be assessed with the KDIGO risk classification.

The KDIGO risk classification predominantly draws upon evidence from Europe and the USA.

This study adds:

This study demonstrated the applicability of the KDIGO risk classification in assessing the risk of cardiovascular events and showed significantly increased risk from the early stages G2A2 and G3aA1 compared with G2A1 by using a large electronic medical record database.

Risks of cardiovascular events, renal outcomes and mortality in Japan were increased along with the KDIGO risk classification.

Potential impact:

Categorizing individuals according to the KDIGO risk classification will be a great utility for better and holistic management of CKD.

The elevated risk of events from the early stages of CKD indicates the importance of early diagnosis and therapeutic intervention through appropriate testing.

The prevalence of chronic kidney disease (CKD) has been increasing in recent years, affecting 850 million people worldwide and 13 million individuals in Japan. In 2017, deaths from CKD reached 1.2 million worldwide, marking a 41.5% increase since 1990 [ 1–3 ]. Therefore, CKD is predicted to become the fifth leading cause of death worldwide by 2040 [ 4 ]. CKD, together with cardiovascular complications and dialysis, is an enormous source of medical care and costs.

Although CKD is asymptomatic in its early stages, renal function declines continuously and progressively, leading to end-stage renal disease (ESRD), which necessitates renal dialysis or transplantation. The progression of CKD is also associated with an increased risk of cardiovascular events, including mortality [ 5 , 6 ]. CKD and cardiovascular diseases share common risk factors, such as diabetes, obesity and hypertension [ 5 ]. The heart and kidney mutually influence each other's functions [ 7 ]. Hence, a clinical condition in one may cause a problem in the other; this is known as cardiorenal syndrome [ 8 ]. Recognizing this while managing CKD is crucial to optimal patient outcomes.

The Kidney Disease: Improving Global Outcomes (KDIGO) risk classification [ 9 ] is a matrix of estimated glomerular filtration rate (eGFR) and urinary protein level as measures of CKD status, and is widely used in the management of CKD in Japan [ 10 ]. Despite the close relationship between CKD and cardiovascular diseases, it is unclear whether the KDIGO risk classification can be directly applied to assess the risk of developing cardiovascular diseases. Moreover, most evidence used to develop the KDIGO risk classification is derived from Western countries, which differ significantly from Japan in terms of lifestyle, genetics and incidence rate of cardiovascular disease. Available evidence regarding kidney disease risk assessment is limited in Japan.

Additionally, although urine protein measurement is recommended in the management of CKD [ 10 ], previous research has demonstrated a low rate of urine protein testing in Japan [ 11 ]. Since a urine protein test is required for KDIGO risk classification, the low testing rate hinders appropriate risk evaluation. This study used a large Japanese database of routine health data in electronic medical records (EMR) to investigate the risk of major adverse cardiovascular events (MACE) based on the KDIGO risk classification in individuals with or without results of urine protein test. The findings of this study have the potential to enhance the management of CKD, ultimately leading to improved patient prognosis and health-related quality of life (HR-QoL).

Study design and data source

This retrospective cohort study used the Real World Data Database (RWD-DB) maintained by the Health, Clinic, and Education Information Evaluation Institute (HCEI, Kyoto, Japan) and JMDC Inc. (Tokyo, Japan) [ 11 ]. The study was performed in accordance with ethical principles that are consistent with the Declaration of Helsinki, and the study protocol and informed consent waiver were approved by the Non-Profit Organization MINS Research Ethics Committee (approval number: MINS-REC-230220); an opt-out approach was adopted.

Study population

Individuals who had two consecutive results of eGFR <90 mL/min/1.73 m 2 at least 90 days apart within a 360-day period (eGFR definitive period) were included ( Supplementary   data, Figs S1 and S2 ). The date of the second eGFR measurement that met the criteria was defined as the index date (1 January 2004–31 December 2020). JSN eGFRcr (referred to as eGFR in this study) was calculated using a previously developed formula [ 12 ]. Individuals aged 18 years or older with a minimum of 360 days of continuous enrollment before the index date (look-back period) were included. The exclusion criteria are shown in Supplementary data, Fig. S1 .

Categorizations into the KDIGO heatmap

The primary exposure was each category within the KDIGO heatmap [ 9 ]. Individuals were categorized into stages G2–G5 based on their eGFR values on the index date and into stages A1–A3 based on their urine albumin/protein levels measured closest to the index date during the eGFR definitive period. Quantitative test results and semi-quantitative results using dipstick grading (–, ±, ≥1+) were both included for the classification of the proteinuria category following this order of priority ( Supplementary data, Fig. S1 ). Individuals who had no test data for urine protein were grouped into the “without urine protein test” group.

Outcome definitions

The detailed definitions are provided in Supplementary data, Table S1 . The primary outcome was the occurrence of MACE, which was defined as a composite of myocardial infarction (MI), stroke, heart failure (HF) hospitalization and in-hospital death (MACE1). Additionally, we established MACE2 as an ad hoc primary outcome designated as a composite of MI hospitalization, stroke hospitalization, HF hospitalization and in-hospital death. The secondary outcome was the renal outcome, a composite of renal replacement therapy, an eGFR decline >50%, an eGFR <15 mL/min/1.73 m 2 , a diagnosis of CKD stage 5 and in-hospital death. Both eGFR and diagnosis by the International Classification of Diseases, 10th Revision codes were used to avoid missing the event of CKD stage 5. The secondary outcome was analyzed in the population excluding individuals who received renal replacement therapy, had an eGFR <15 mL/min/1.73 m 2 , or had a diagnosis of CKD stage 5 on or before the index date. The primary and secondary composite endpoints were analyzed as time-to-first event. Individuals were followed until the occurrence of the outcome of interest, the last available data in the database, 30 September 2021, 1800 days after the index date, or death, whichever came first.

Statistical analysis

Categorical variables are presented as numbers and percentages, while continuous data are summarized as the number of non-missing observations and presented as the mean ± standard deviation (SD). Missing values were not imputed for any of the variables.

The Kaplan–Meier estimator, with Greenwood's formula, was used to analyze the cumulative event-free survival and 95% confidence intervals (CI) of the outcomes. The crude incidence rate and 95% CI were calculated for each outcome, assuming a Poisson distribution. The hazard ratio (HR) and 95% CI of each KDIGO heatmap, for which G2A1 was used as a reference, were estimated using Cox proportional hazards models with adjustments for selected covariates (Supplementary Methods, Supplementary data, Tables S2 and S3 ). All analyses were performed using Python 3.7.9 (Python Software Foundation, Wilmington, DE, USA) and R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).

Baseline characteristics

This study included 543 606 individuals who met the eligibility criteria (Table  1 and Supplementary data, Fig. S1 ). Of these, 222 246 (40.9%) had no urine protein data (designated as “without urine protein test” group), and the rest of the individuals were categorized into the KDIGO heatmap according to their eGFR and urine protein test results. The mean age ± SD of the overall population was 61.6 ± 15.3 years, and 50.1% were male. The largest gap of 12 years was observed in between G2 (58.4 ± 14.7 years) and G3a (71.3 ± 11.8 years). The mean age continued to increase toward G3b (77.1 ± 10.8 years) and G4 (77.4 ± 12.1 years), and then decreased in G5 (69.5 ± 13.7 years). There were no difference in mean age from A1 (59.2 ± 14.3 years) to A2 (59.2 ± 16.0 years), and a 6-year gap to A3 (65.2 ± 16.4 years).

Baseline characteristics.

The prevalence of diabetes mellitus and hypertension increased with the progression of eGFR and proteinuria stages. The use of renin–angiotensin–aldosterone system inhibitors and diuretics trended upwards to stage G4, then plateaued, and calcium channel blockers increased up to stage G5 ( Supplementary data, Table S4 ).

Incidence rate of MACE

The event-free survival for the primary outcome MACE1 exhibited a nearly linear decrease during the 1800-day follow-up period (Fig.  1 a). There was no marked difference in the event rates between the stages G4 and G5 throughout the follow-up period. Similarly, the event-free survival for ad hoc primary outcome MACE2 (see Materials and methods for details) also linearly decreased in all eGFR stages (Fig.  1 b). In both MACE1 and MACE2, fewer events were observed in A1 (normal to mildly increased) than in A2 (moderately increased) and A3 (severely increased) ( Supplementary data, Figs S3 and S4 ). The incidence rates of MACE1 and MACE2 were generally higher in individuals with more advanced eGFR stages, with the exception of G5 ( Supplementary data, Table S5 ). Each component of MACE exhibited a similar trend; however, in the advanced eGFR stages, a few or no events were observed in MI hospitalization and stroke hospitalization.

Event-free survival from MACE by KDIGO eGFR stages. ( a ) Primary outcome MACE1; ( b ) ad hoc primary outcome MACE2.

HR for MACE

The adjusted HRs, using stage G2A1 as a reference, are shown in Table  2 . The risk of MACE1 increased with stage progression of CKD in both eGFR and proteinuria, and the increase was significant from the early stages G3aA1 and G2A2 with HRs of 1.16 (95% CI 1.12–1.20) and 1.17 (95% CI 1.12–1.21), respectively, to the highly advanced stage G5A3 with an HR of 2.83 (95% CI 2.54–3.15, Table  2 a). The risk of MACE2 also significantly increased in the early stages of G3aA1 and G2A2 with HRs of 1.17 (95% CI 1.11–1.23) and 1.35 (95% CI 1.28–1.43), respectively (Table  2 b). Similar results were obtained in two sensitivity analyses using the “strict” classification of proteinuria based on only quantitative data ( Supplementary data, Table S6 a and b) and in individuals having any urine protein data excluding the “without urine protein test” group ( Supplementary data, Table S7 a).

HRs for MACE in KDIGO stages.

The risk also increased in components of both MACE1 and MACE2 in the advanced stages of eGFR and proteinuria stages (Table  3 ). A 3- to 5-fold higher risk of HF hospitalization was observed in G4, and an approximately 4-fold higher risk of in-hospital death was observed in G5; both outcomes had higher HRs generally than MI and stroke. The risks of MI hospitalization and stroke hospitalization increased from the early stage G3aA1 with HRs of 1.39 (95% CI 1.11–1.73) and 1.23 (95% CI 1.10–1.37), respectively. The risk further increased with advancing eGFR stage among those without urine protein test. Similar results were observed in the sensitivity analysis of MACE components using the “strict” cohort ( Supplementary data, Table S8 ).

HRs for the components of MACE.

Data are HR (95% CI).

Components of MACE1.

Components of MACE2.

NA, not applicable due to no events observed.

Incidence rate of renal outcome

Event-free survival for renal outcome got lower with progression in the eGFR stage throughout the 1800-day follow-up period (Fig.  2 ), with a rapid and large decrease in G4 (the most advanced stage in this analysis). Across all eGFR stages, increased event rates of renal outcome were observed with the progression of the proteinuria stage ( Supplementary data, Fig. S5 and Table S9 ).

Event-free survival from renal outcome by KDIGO eGFR stages.

HR for renal outcome

The risk of renal outcome significantly increased from the early stages G3aA1 and G2A2, with HRs of 1.29 (95% CI 1.22–1.36) and 1.53 (95% CI 1.44–1.62), respectively (Table  4 ). A 6- to 20-fold higher risk of renal outcome was observed in stages G4A1–G4A3. The risk also increased in all renal outcome components, with worsening eGFR and proteinuria stages (Table  5 ). Similar results were also obtained in two sensitivity analyses using a “strict” classification ( Supplementary data, Table S6 c) and in individuals excluding the “without urine protein test” group ( Supplementary data, Table S7 b).

HRs for renal outcome in KDIGO stages G2–G4.

NA, not applicable.

HRs for the components of renal outcome in KDIGO stages G2–G4.

The KDIGO classification, originally developed based on the risk of death, ESRD and cardiovascular death in people with CKD [ 9 ], predominantly draws upon evidence from Europe and the USA. To the best of our knowledge, this study is the first observational study in Japan involving a substantial number of study participants who demonstrate increased risks of MACE, ESRD and mortality with progression of both eGFR and proteinuria stages based on the KDIGO heatmap. While people in G3–G4 were slightly older than those previously reported in Japanese CKD cohorts, consistent findings that mean age increased as eGFR stage progressed, with the largest gap between G2 and G3a [ 13–15 ], were provided in the present study. Furthermore, the patient distribution across eGFR stages and the prevalence of proteinuria were similar to those estimated as for all over Japan [ 3 ], supporting the notion that population examined in the present study represents Japanese clinical settings.

The risks associated with MI, stroke, HF and in-hospital death increased concomitantly with the advancement of eGFR and proteinuria stages in both MACE1 and MACE2. The increased risk was similar to that reported in the CKD Prognosis Consortium [ 16 ]. Although some uncertainty remains in MI hospitalization and stroke hospitalization due to few to no events in the advanced eGFR stages, e.g. no event in G5A1, the risk of each component showed a similar trend as the composite MACE. In particular, the adjusted HR for HF hospitalization significantly increased with decreasing eGFR and worsening urinary protein levels, suggesting a strong association between CKD progression and HF events. This is consistent with a previous report [ 17 ] showing that the development of HF in people with CKD in Japan was associated with eGFR stage progression. In the same study [ 17 ], the incidence of total mortality in stage G4 was higher than that in G5. By categorizing individuals according to their proteinuria level, the current study showed that the incidence and adjusted HR of in-hospital death increased as the eGFR stage progressed, with the highest at G5. These results demonstrate the prognostic utility of the KDIGO heatmap on MACE, emphasizing the significance of regular assessments of eGFR and urine protein for risk assessment through the KDIGO classification, in conjunction with accurate diagnosis for the effective management of CKD.

The risk of unfavorable renal outcomes also increased with CKD progression, as in the case of MACE. The magnitude of increase in risk seems somewhat small compared with that of CKD Prognosis Consortium [ 16 ]; this might be explained by residual confounding factors for HR calculation, suggesting potential underestimation of risk in the present study. Another possible explanation is differences in terms of lifestyle, genetics, patient care and medical environment between Japan and other countries included in CKD Prognosis Consortium. Nonetheless, the risk increase was inarguably high in the present study, e.g. HR for renal replacement therapy in G5A3 was 138.

The increased risk of renal events became more pronounced with the progression of proteinuria stages, as corroborated by a previous meta-analysis [ 16 , 18 ]. In Japan, diabetic nephropathy is the primary cause of dialysis, accounting for approximately 40% [ 19 ]. Diabetic nephropathy is considered to develop typically with progressive albuminuria and a decline in renal function. Additionally, previous studies have confirmed that proteinuria itself is a risk factor for the progression of renal dysfunction leading to ESRD [ 20–22 ]. In the present study, HRs for renal outcome were generally higher in individuals having proteinuria within the same eGFR stage. Particularly, HR for renal replacement therapy increased up to approximately 10-fold in the early stage G2A3, demonstrating that proteinuria is associated with subsequent risk of ESRD regardless of cause, as previously reported [ 23 ]. Several randomized controlled trials have shown the association between reduced urinary albumin and reduced risk of dialysis [ 24–26 ], and CKD management guidelines recommend the measurement of urine albumin for prognostic purposes [ 9 ], highlighting the importance of interventions targeting proteinuria reduction to mitigate the need for dialysis. Given the substantial impairment of HR-QoL and the burden on caregivers, in addition to the economic burden due to lost productivity and high medical costs, many countries are striving to prevent the need for dialysis [ 27 ].

Although the importance of urinalysis is evident, challenges remain in its implementation. For example, a multicenter observational study in the USA that involved 9307 individuals with type 2 diabetes mellitus and a 15-month follow-up of their medical records reported that more than half of them were not tested for urine protein by dipstick, and awareness of CKD remained low [ 28 ]. Similarly, in the present study, about 40% of the participants had no urine protein test results. The risk in this subgroup was high, with HRs ranging from 1.39 (G2) to 3.18 (G5) for MACE1. This fact underscores the critical need for urinary protein testing to assess risk and optimize management.

The KDIGO heatmap serves not only as a tool for assessing the risk of clinical events but also as a criterion for referral to a nephrologist. Early referral has been reported to result in a better prognosis than referral at an advanced stage [ 29 ]. For the diagnosis of CKD, measurement of eGFR and urine protein is essential, especially in the early stage G2; urine protein test is important since only eGFR data are insufficient to diagnose CKD. Additionally, the progression from G2A1 to G2A2 seems to be faster than that to G3aA1: the mean age was 56.9 ± 13.7 years for G2A1, 55.6 ± 14.9 years for G2A2 and 69.2 ± 11.5 years for G3aA1, further supporting an importance of examining urine protein in stage G2. As shown in this study, a much easier dipstick test may be useful for the risk assessment of CKD. A semi-quantitative test is applicable to screening, and subsequent quantitative determination of urine protein will be preferable.

Identifying CKD is the first step to manage the disease and slow its progression [ 30 ]; however, the diagnosis rate of CKD is very low in the early stages (G2 and G3a), at approximately 10% [ 11 , 31 ]. This may be due to the absence of clinical symptoms in the early stages in combination with the common misconception that declining renal function is a result of aging among older people [ 32 , 33 ]. Furthermore, the slower rate of renal function decline in females may account for the lower diagnosis rate of CKD in females than in males [ 34–37 ]. Notably, the present study showed a significantly increased risk of events in the early stages (G3aA1 and G2A2) for both MACE and renal outcomes. It has also been reported that as CKD progresses, the healthcare costs required for its management increase [ 38 ]. Hence, clinical inertia may cause adverse outcomes and adverse health and economic consequences.

In recent years, sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) have drawn attention as promising treatments for CKD, with many studies demonstrating their renal and cardiovascular benefits [ 26 , 39–41 ]. In the present study, an increased risk of developing cardiovascular disease was observed with CKD progression, indicating the importance of treatment with awareness of the cardiorenal interaction. Several studies showed that SGLT2 inhibitors and MRAs can not only prevent the progression but also improve urine protein category [ 42–45 ], which will result in reducing the risk of cardiovascular events [ 39 , 46 ]. Both SGLT2 inhibitors and MRAs are also recommended in guidelines as standard treatments for HF [ 47–49 ]. Dapagliflozin, an SGLT2 inhibitor, reduces the risk of kidney failure and cardiovascular death/HF hospitalization and prolongs survival in people with CKD, regardless of the presence of type 2 diabetes [ 50 ]. The KDIGO 2024 Clinical Practice Guideline [ 51 ] recommend the use of SGLT2 inhibitors in people with CKD exhibiting proteinuria with or without diabetes. These therapeutic options are expected to slow the progression of renal function decline and prevent cardiovascular events and mortality.

This study used an EMR database. The interpretation and generalization of study results should be made cautiously because the data used in this study may not fully reflect the clinical practice in Japan, as it was sourced from contracted medical institutions (i.e. not random sampling). Additionally, diagnostic accuracy could vary among diseases, as the diagnoses in the data were derived from routinely collected health data and included diagnoses made for insurance claims; therefore, there is a possibility that they may differ from actual diagnoses. Furthermore, the data were not originally collected for research purposes; hence, there were some missing values. Specifically, urinary protein measurements were performed in individuals only when deemed necessary, and the KDIGO heatmap assessment may be affected by channeling bias. However, we adjusted for a sufficient number of covariates to mitigate this issue. Lastly, because the database was anonymized for medical institutions, no follow-up was available after individuals were transferred to other healthcare facilities, which may have caused an underestimation of the outcomes considered in this study. We assumed that eligible individuals were included in the data only once in this study; however, they may have been re-registered at other centers after transfer, potentially introducing duplications.

This study is the first to demonstrate the applicability of the KDIGO risk classification in assessing the risk of cardiovascular events and renal outcomes in Japan by using a large clinical database. The risk of events is increased from the early stages of CKD (G3aA1, G2A2), indicating the importance of early diagnosis and therapeutic intervention through appropriate testing. These insights may contribute to event reduction and HR-QoL improvement by enhancing the management of CKD in clinical practice.

This study was approved by the Non-Profit Organization MINS Research Ethics Committee. All authors thank the HCEI for the RWD-DB development. We are grateful to Hiroo Tsubota and Akira Sakamoto from AstraZeneca KK for valuable comments and logistic support; and Keiji Yokota from Real World Data Co., Ltd for his significant contribution to the data analysis. The authors thank Editage ( www.editage.jp ) for English editing.

H.A., M.H. and A.O. contributed to conceptualization, project administration, methodology, data interpretation and funding acquisition. S.I., S.K. and K.S. participated in data curation, resources, methodology, investigation, formal analysis and validation. A.O. supervised the study. S.M. and T.T. contributed to data interpretation and provided clinical perspectives. All authors contributed important intellectual content during manuscript drafting or revision and approved the final manuscript.

The dataset used in the study cannot be shared publicly because the data was obtained from JMDC Inc. The data will be available on reasonable request to the corresponding author with the permission of JMDC Inc.

The study was sponsored by AstraZeneca KK. H.A., M.H. and A.O. are employees of AstraZeneca KK. S.I., S.K. and K.S. are employees of Real World Data Co., Ltd, a healthcare analytics company that received funding for this research from AstraZeneca KK. S.M. and T.T. have received fees for lectures by AstraZeneca KK.

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• proteinuria
• kidney failure, chronic
• cardiovascular system
• urine protein test
• cardiovascular event

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• v.2015; 2015

17-Year-Old Boy with Renal Failure and the Highest Reported Creatinine in Pediatric Literature

Vimal master sankar raj.

1 Department of Pediatric Nephrology, University of Illinois College of Medicine at Peoria (UICOMP), Peoria, IL 61603, USA

Jessica Garcia

2 Department of Pediatrics, University of Illinois College of Medicine at Peoria (UICOMP), Peoria, IL 61603, USA

Roberto Gordillo

The prevalence of chronic kidney disease (CKD) is on the rise and constitutes a major health burden across the world. Clinical presentations in early CKD are usually subtle. Awareness of the risk factors for CKD is important for early diagnosis and treatment to slow the progression of disease. We present a case report of a 17-year-old African American male who presented in a life threatening hypertensive emergency with renal failure and the highest reported serum creatinine in a pediatric patient. A brief discussion on CKD criteria, complications, and potential red flags for screening strategies is provided.

1. Background

Prevalence of chronic kidney disease (CKD) is increasing significantly and it has poor outcomes if not diagnosed and treated early in its course [ 1 ]. CKD is a public health issue that affects 9 to 12% of the population in the USA [ 2 , 3 ]. When management is early and adequate, the rate of progression to kidney failure can be slowed, comorbidities prevented, and the morbidity and mortality of cardiovascular disease associated with CKD decreased. There is lack of information on incidence and prevalence of earlier stages of CKD in children, as most of these patients are asymptomatic [ 4 ].

The National Kidney Foundation (NKF) created the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines and definition of CKD to facilitate the diagnosis and management by primary care physicians. Serum creatinine, a product of muscle metabolism, has been widely used as a marker for glomerular filtration rate (GFR). We describe a clinical case of an adolescent male with the highest serum creatinine reported in a pediatric patient. The primary aim of this case report was to create awareness of chronic kidney disease among general practitioners and to stress that clinical manifestations could be subtle in the early stages of the disease.

2. Case Presentation

A 17-year-old African American male who was previously healthy with the exception of high blood pressure presented to a referring hospital with a 4-day history of coughing, vomiting, headache, facial edema, and lower extremity cramping. One day prior to admission, he also had noticed decreased urine output. At the referring hospital, he was found to be hypertensive with a serum creatinine of 52 mg/dL (4597  µ mol/L) and was transferred to our pediatric intensive care unit for further evaluation and treatment.

Patient was born at term gestation and there were no significant health problems. Patient during his routine clinic visits was noted to have high blood pressure by his primary care physician but no further evaluation was done as the blood pressure was attributed to his obesity. Patient did not have any prior surgeries and was not taking any medications. There was no significant history of renal disease, dialysis, or kidney transplant in any of the family members.

On admission, patient was noted to be afebrile, hypertensive with blood pressure of 179/93 mm Hg and heart rate of 88 beats per minute, and tachypneic with respiratory rate in the 40s but saturating at 100% on room air. His anthropometric measurements showed his height to be 180 cm, his weight to be 115 kg, and body mass index to be >99%. Pertinent positives in physical exam include obesity, respiratory distress with nasal flaring, bilateral periorbital edema, and bilateral lower extremity edema. Laboratory results showed the patient to have azotemia with blood urea nitrogen (BUN) of 203 mg/dL and serum creatinine of 52 mg/dL, measured by enzymatic method. He had severe metabolic acidosis with bicarbonate of 10 mmol/L. Patient also had severe electrolyte imbalances including hyponatremia (126 mmol/L), hyperkalemia (6.3 mmol/L), hyperphosphatemia (10.5 mg/dL), hypocalcemia (5.3 mg/dL), and severe anemia with hemoglobin at 5.1 g/dL. Parathyroid hormone levels were elevated at 682 pg/mL (normal 11–80 pg/mL). Urine dipstick showed 3+ protein and 2+ blood and a urine protein to creatinine ratio was elevated at 14 (normal <0.2). Serological workup including complement levels, antinuclear antibodies, antinuclear cytoplasmic antibodies, and antiphospholipid antibodies was negative. Chest X-ray was significant for cardiomegaly and pulmonary edema. Echocardiogram showed severe left ventricular hypertrophy. Renal ultrasound revealed bilateral small, echogenic kidneys (right kidney 7.7 × 5.2 × 4.8 cm; left kidney 8.7 × 4.3 × 4.1 cm) consistent with dysplastic kidneys. Patient emergently underwent hemodialysis for fluid overload and to correct electrolyte imbalance. His anemia and electrolyte imbalances were slowly corrected. He is currently transitioned to peritoneal dialysis awaiting kidney transplant.

3. Discussion

CKD is a heterogeneous group of diseases with altered structure and function of the kidneys with varying manifestation based on underlying etiology. Based on KDIGO guidelines, CKD is classified into various stages using GFR and the degree of albuminuria (Tables ​ (Tables1(a) 1 (a) and ​ and1 1 (b)).

(a) CKD based on GFR [ 14 ]. (b) Persistent albuminuria and risk for CKD [ 14 ].

(a)  

(b)  

Adapted from KDIGO 2012.

The modified Schwartz formula used to calculate GFR is derived from the CKiD (chronic kidney disease in children) [ 5 ] and uses the following formula:

•   eGFR = K (height in centimeters)/Serum creatinine with the constant K value being 0.413.

GFR varies with age, gender, and body size and increases from infancy to adulthood. Normative data of GFR based on age is presented in Table 2 . This needs to be taken into consideration on CKD classification in pediatric population.

Normal glomerular filtration rate (GFR) in children and adolescents [ 15 ].

Adapted from National Kidney Foundation.

4. Epidemiology

Most epidemiological information on adult CKD is available from data on ESRD patients [ 6 ]. This represents only the tip of the iceberg and the actual incidence of early stage CKD will be much higher. The exact prevalence of childhood CKD is unknown but it has been estimated at 82 cases per million with ESRD around 15 cases per million based on national registries [ 7 – 9 ]. Though pediatric ESRD contributes only 2% to the total ESRD burden, the mortality rate in adolescents is about 30 to 150% higher compared to the general population [ 8 , 10 ] indicating the need for specialized care. The expected remaining life time of children below 14 years of age with ESRD and on dialysis calculated per US renal data system (USRDS) [ 8 ] is only 20 years. Hence, the importance of primary prevention with early detection and aggressive intervention cannot be overstated.

5. Etiology

The etiology for ESRD varies with age. Structural anomalies contribute to a large degree to ESRD in younger children, while it is predominantly glomerular diseases in older children. As per NAPRTCS 2011 review data, about 14.2% of all pediatric dialysis patients had ESRD secondary to hypoplastic/dysplastic kidney with obstructive uropathy at 12.6% ( Table 3 ).

Pediatric dialysis patient demographics [ 16 ].

Adapted from NAPRTCS 2011.

6. Screening Strategies for CKD

Screening strategies are aimed at early detection and intervention for CKD so as to slow the progression of disease. Though routine urine screening for CKD has not been found to be cost effective in the general population and has not been recommended by AAP, it is important to identify and screen children at high risk. Some of the high risk populations at risk for CKD are mentioned below:

• Prematurity and being small for gestational age.
• Congenital abnormalities of the kidney and urinary tract.
• H/o poor growth or failure to thrive.
• Family history of kidney diseases and relatives on dialysis or transplant.
• Electrolyte or acid-base abnormalities.
• Body mass index (BMI) > 95th percentile.
• Blood pressure greater than the 95% recorded on multiple visits.
• Polyuria or inappropriately dilute urine.
• Gross hematuria.
• Dysfunctional voiding, urinary incontinence, or prolonged enuresis.
• H/o recurrent UTI.

A thorough history and physical examination during well child visits could help us in identifying these children with high risk for kidney disease. Once identified, these children should have their urine checked for proteinuria, their renal function analyzed by measuring creatinine, and their blood pressure regularly screened. Children with evidence of kidney damage should be sent to a specialist for further investigation and treatment. For our patient, blood pressure > 95% and the BMI > 95% should have prompted a screening for potential kidney disease.

7. CKD Complications

Cardiovascular disease accounts for most deaths in pediatric CKD similar to adult onset CKD. In contrast to adult CKD patients, where atherosclerosis and coronary vascular disease are much more common, arrhythmias account for the majority of cardiovascular death in children (19.6%) [ 11 ]. Traditional risk factors for CVD such as dyslipidemia and hypertension along with nontraditional risk factors such as anemia, disorders of calcium phosphorus metabolism, and increased chronic inflammation are highly prevalent in CKD population. These also contribute significantly to the cardiovascular burden in these children.

Anemia is a common complication in CKD secondary to impaired erythropoiesis. As CKD progresses, so does the prevalence of anemia in these children. Factors such as malnutrition, blood loss, iron deficiency, inadequate dialysis, and uncontrolled secondary hyperparathyroidism should always be kept in mind while managing resistant anemia. KDIGO recommends maintaining hemoglobin levels between 10 and 12 g/dL to reduce need for transfusion. Iron levels should be checked and adequately supplemented in all CKD patients before initiating or increasing dose of erythropoiesis stimulating agents.

Metabolic bone disorder (CKD-MBD) is a major complication in CKD. This occurs secondary to the inability of kidneys to excrete phosphorus and synthesize active vitamin D. Net result is secondary hyperparathyroidism. Disorders in calcium phosphorus balance and secondary hyperparathyroidism play a major role in vascular calcification in CKD and subsequent cardiovascular mortality and morbidity.

Fluid and electrolyte imbalances are especially common in children with CKD secondary to congenital anomalies of the kidneys and urinary tract (CAKUT). In CAKUT impaired urinary concentrating ability could present with polyuria and can present with dehydration. Disorder of sodium, potassium, and acid-base balance is also very common in these children due to impaired tubular handling. As the normal tubular response to ADH is not present, special attention should be paid to the fluid and electrolyte replacement in these children in the setting of dehydration.

Growth failure and neurocognitive delay are important concerns for young children with CKD [ 12 , 13 ]. Providing adequate calories and protein intake are important in children with CKD as they are more prone to muscle wasting and anorexia. Factors such as systemic inflammation, oral aversion, and alteration in hormonal levels or resistance to action of hormones (follicle stimulating hormone, luteinizing hormone, growth hormone, and thyroid hormone) also contribute to short stature and CKD in children. In infants and toddlers with CKD to maximize nutritional intake a gastrostomy tube is often placed to provide adequate calories and fluids. Optimal nutrition and use of growth hormone replacement are often needed in children with CKD to ensure that they reach their growth potential.

8. Conclusion

Our patient had bilateral dysplastic kidneys and ultimately progressed to ESRD. Though he had potential red flags including obesity and high blood pressure noted on multiple occasions, the thought of kidney disease was not entertained. A screening urine dipstick could have prevented this life threatening admission with hypertensive emergency, severe anemia, and multiple electrolyte imbalances. Earlier detection of kidney disease and control of hypertension and proteinuria could have slowed the progression of disease and also would have allowed the time to plan for his renal replacement therapy in a safe manner. Chronic kidney disease is a growing health burden and awareness of it among primary care physicians is essential in early diagnosis and treatment.

Abbreviations

The authors have no financial relationships relevant to this paper to disclose.

Conflict of Interests

The authors declare that there is no conflict of interests to disclose.

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• Therapeutic drug monitoring of inhaled tobramycin in a patient with chronic kidney disease
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• Rebeca Añez-Castaño 1 ,
• http://orcid.org/0000-0002-3950-7250 Carles Iniesta-Navalón 1 , 2 ,
• Miguel Almanchel-Rivadeneyra 1 ,
• Eva García-Villalba 3 ,
• Eva Oliver-Galera 3 ,
• Lorena Rentero-Redondo 1 , 2
• 1 Department of Hospital Pharmacy , Reina Sofia University General Hospital , Murcia , Spain
• 2 Clinical Pharmacokinetics and Applied Pharmacotherapy Group , Instituto Murciano de Investigación Biosanitaria (IMIB-Pascual Parrilla) , El Palmar , Spain
• 3 Department of Infectous Disease , Reina Sofia University General Hospital , Murcia , Spain
• Correspondence to Dr Carles Iniesta-Navalón; carles424{at}hotmail.com

This case report investigates elevated serum concentrations of inhaled tobramycin in a patient with chronic kidney disease. The patient, a man in his early 80s with complex comorbidities, underwent tobramycin inhalation therapy for chronic respiratory infections caused by Pseudomonas aeruginosa . Despite the strategic localised treatment approach, unexpectedly high plasma tobramycin concentrations were observed. After a dosage adjustment guided by a pharmacokinetic-pharmacodynamic model, a final inhalation dose of 300 mg of tobramycin was determined at a 24-hour interval. This case report underscores the need for rigorous monitoring of plasma tobramycin levels in patients with renal impairment undergoing inhaled tobramycin therapy, advocating for enhanced pharmacokinetic models to improve the safety and efficacy of the treatment.

• Pharmacokinetics
• Kidney Failure, Chronic
• Case Reports
• Drug Monitoring

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All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/ejhpharm-2023-004075

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Anemia and Chronic Kidney Disease

What is anemia.

Anemia happens when your red blood cells are in short supply. Red blood cells carry oxygen from your lungs to all parts of your body, giving you the energy you need for your daily activities.

What are the symptoms of anemia?

Anemia can cause you to:

• Have little energy for your daily activities
• Have a poor appetite
• Have trouble sleeping
• Have trouble thinking clearly
• Feel dizzy or have headaches
• Have a rapid heartbeat
• Feel short of breath
• Feel depressed or "down in the dumps"

Why do people with kidney disease get anemia?

Your kidneys make an important hormone called erythropoietin (EPO) . Hormones are chemical messengers that travel to tissues and organs to help you stay healthy. EPO tells your body to make red blood cells. When you have kidney disease, your kidneys cannot make enough EPO. Low EPO levels cause your red blood cell count to drop and anemia to develop.

Most people with kidney disease will develop anemia. Anemia can happen early in the course of kidney disease and grow worse as kidneys fail and can no longer make EPO. Anemia is especially common if you:

• Have diabetes
• Are African-American/Black
• Have moderate or severe loss of kidney function ( CKD stage 3 or 4)
• Have kidney failure (stage 5)

Check out our online communities to connect, learn more and hear from others going through similar experiences.

How do i know if i have anemia.

Not everyone with anemia has symptoms. If you have kidney disease, you should have a blood test to measure your hemoglobin level at least once a year to check for anemia. Hemoglobin is the part of red blood cells that carries oxygen throughout your body. If your hemoglobin is too low, it is likely you have anemia. In that case, your healthcare provider will check to find the exact cause of your anemia and plan a treatment that is right for you.

How do you treat anemia?

Your treatment will depend on the exact cause of your anemia.

If your anemia is due to kidney disease, your healthcare provider will treat you with:

• Drugs called erythropoiesis stimulating agents (ESAs) ESAs help your body make red blood cells. Your healthcare provider will give the ESA to you as an injection under the skin.
• Extra iron Your body also needs iron to make red blood cells—especially when you are receiving ESAs. Without enough iron, your ESA treatment will not work as well. Your healthcare provider may give you iron to take as a pill. Another way to receive iron is directly into a vein in your doctor's office or clinic.

For more information please view our full PDF brochures or request a free copy by calling 855.NKF.CARES ( 855.653.2273 ) or email [email protected] .

• Anemia and Iron Needs in Dialysis

If you would like more information, please contact us .

© 2015 National Kidney Foundation. All rights reserved. This material does not constitute medical advice. It is intended for informational purposes only. Please consult a physician for specific treatment recommendations.

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• Disease activity of rheumatoid arthritis and kidney function decline: a large prospective registry study
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• http://orcid.org/0000-0002-3082-1374 Sho Fukui 1 , 2 , 3 ,
• Wolfgang C Winkelmayer 4 ,
• http://orcid.org/0000-0001-9475-1363 Sara K Tedeschi 1 ,
• http://orcid.org/0000-0001-9157-4269 Javier Marrugo 1 ,
• Hongshu Guan 1 ,
• Leslie Harrold 5 , 6 ,
• Heather J Litman 6 ,
• Tomohiro Shinozaki 7 ,
• http://orcid.org/0000-0001-8202-5428 Daniel H Solomon 1
• 1 Division of Rheumatology, Inflammation, and Immunity , Brigham and Women's Hospital and Harvard Medical School , Boston , Massachusetts , USA
• 2 Department of Emergency and General Medicine , Kyorin University , Tokyo , Japan
• 3 Immuno-Rheumatology Center , St. Luke’s International Hospital , Tokyo , Japan
• 4 Selzman Institute for Kidney Health, Section of Nephrology , Baylor College of Medicine , Houston , Texas , USA
• 5 Medicine , University of Massachusetts Medical School , Worcester , Massachusetts , USA
• 6 CorEvitas LLC , Waltham , Massachusetts , USA
• 7 Department of Information and Computer Technology, Faculty of Engineering , Tokyo University of Science , Katsushika-ku , Tokyo , Japan
• Correspondence to Dr Sho Fukui; sfukui{at}bwh.harvard.edu ; Professor Daniel H Solomon; dsolomon{at}bwh.harvard.edu

Introduction Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain.

Method We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR<60 mL/min/1.73 m 2 ) and stage G3b (eGFR<45 mL/min/1.73 m 2 ). Results were adjusted for relevant time-fixed and time-varying covariates.

Results 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m 2 ) contributed 234 973 visits and 146 778 person-years of follow-up. Multivariable mixed-effect linear model showed an average annual eGFR decline during follow-up in the TA-CDAI-remission group of −0.83 mL/min/1.73 m 2 and estimated additional annual declines (95% CI) of –0.09 (–0.15 to –0.03) in low, –0.17 (−0.23 to –0.10) in moderate and −0.18 (–0.27 to –0.08) mL/min/1.73 m 2 in high disease activity patients. Compared with TA-CDAI remission, adjusted HRs (95% CI) for CKD stage G3a during follow-up were 1.15 (1.01 to 1.30) in low, 1.22 (1.06 to 1.40) in moderate and 1.27 (1.05 to 1.52) in high disease activity; for CKD stage G3b, 1.22 (0.84 to 1.76) in low, 1.66 (1.12 to 2.45) in moderate and 1.93 (1.16 to 3.20) in high disease activity.

Conclusions Higher RA disease activity was associated with accelerated eGFR decline and increased risk of clinically relevant kidney dysfunction. Future intervention studies should attempt to replicate the association between RA disease activity and eGFR.

• Rheumatoid Arthritis
• Epidemiology
• Arthritis, Rheumatoid
• Atherosclerosis

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https://doi.org/10.1136/ard-2024-226156

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Handling editor Josef S Smolen

Contributors SF and DHS contributed to the original conception and design of this study, which WCW, SKT, JM, LH, HJL and TS reviewed and corrected. SF and HG collected data. SF performed data analysis with supervision from LH, HJL, TS and DHS. SF, WCW, SKT, JM and DHS initially interpreted the data, and other authors advised on the interpretation. SF drafted the original manuscript, which was critically reviewed and revised by all other authors. All authors have read and approved the final version of the manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. SF is the guarantor.

Funding This study was supported by funding from National Institute of Arthritis and Musculoskeletal and Skin Diseases P30 AR072577 (PI: DHS).

Competing interests WCW reports having served as a scientific advisor or consultant to Actos, Akebia, Ardelyx, AstraZeneca, Bayer, Cadrenal, GlaxoSmithKline, Lilly, Merck, Natera, Pharmacosmos, Unicycive, Vera and Zydus. SKT reports consulting fees from Novartis. LH reports employment of CorEvitas, consultant to AbbVie, Bristol Myers Squibb, Pfizer, Roche and speakers bureau for Bristol Myers Squibb. DHS reports salary support through research contracts to his institution from CorEvitas, Janssen and Novartis.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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