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In Sri Lanka, an endemic of chronic kidney disease of unknown origin (CKDu) is affecting rural communities. The endemic has similarities with Mesoamerican Nephropathy (MeN) in Central America, however it has not yet been clarified if the endemics are related diagnostic entities. We designed this study of kidney biopsies from patients with CKDu in Sri Lanka to compare with MeN morphology. Eleven patients with CKDu were recruited at the General Hospital, Polonnaruwa, using similar inclusion and exclusion criteria as our previous MeN studies. Inclusion criteria were 20-65 years of age and plasma creatinine 100-220 μmol/L. Exclusion criteria were diabetes mellitus, uncontrolled hypertension and albuminuria >1g/24h. Kidney biopsies, blood and urine samples were collected, and participants answered a questionnaire. Included participants were between 27-61 years of age and had a mean eGFR of 38±14 ml/min/1.73m2. Main findings in the biopsies were chronic glomerular and tubulointerstitial damage with glomerulosclerosis (8-75%), glomerular hypertrophy and mild to moderate tubulointerstitial changes. The morphology was more heterogeneous and interstitial inflammation and vascular changes were more common compared to our previous studies of MeN. In two patients the biopsies showed morphological signs of acute pyelonephritis but urine cultures were negative. Electrolyte disturbances with low levels of serum sodium, potassium, and/or magnesium were common. In the urine, only four patients displayed albuminuria, but many patients exhibited elevated α-1-microglobulin and magnesium levels. This is the first study reporting detailed biochemical and clinical data together with renal morphology, including electron microscopy, from Sri Lankan patients with CKDu. Our data show that there are many similarities in the biochemical and morphological profile of the CKDu endemics in Central America and Sri Lanka, supporting a common etiology. However, there are differences, such as a more mixed morphology, more interstitial inflammation and vascular changes in Sri Lankan patients.

In this mini review, we would like to challenge the well-established ‘fact’ that lead exposure causes chronic renal failure (CRF). Even though only scarce evidence exists of the relationship between lead and renal failure, a World Health Organization Environmental Health Criteria document summarizes that ‘Lead has been a very common cause of acute or chronic renal failure’. It is also written and cited in textbooks and numerous publications that chronic lead nephropathy causes a slowly progressive interstitial nephritis manifested by a reduced glomerular filtration rate, and that there is a growing consensus that lead contributes to hypertension in the general population. We will argue that, when published reports are carefully scrutinized, such statements on lead and CRF are not evidence based but are rather founded on a few narrative reports on lead-exposed individuals and statistical associations between lead and serum creatinine (or urea) in a few population studies. We will, however, not argue that lead is not toxic and that lead does not cause other types of severe health effects where the evidence is unquestionable, but we do not believe that the kidneys are an early victim after lead exposure.

Objectives: The aim of this study was to determine the no observed adverse effect level (NOAEL), the lowest observed adverse effect level (LOAEL) and the benchmark dose low (BMDL) of cadmium exposure by re-evaluation of the dose–response relationship between cumulative cadmium exposure and renal tubular damage reported previously. Methods: The participants were workers (326 men and 114 women) employed for at least three months between 1931 and 1982. Blood cadmium (Cd-B) and air cadmium (Cd-A) were collected at regular intervals with urinary β2-microglobulin as the tubular effect marker. Cumulative Cd-A and Cd-B were estimated by multiplying concentration and working period. The BMDL was calculated using Benchmark Dose Software (version 3.1.2). The benchmark response (BMR) was set at 5% or 10%. Results: By logistic regression, the NOAEL of mean cumulative Cd-B was 7122 months nmol/L. The LOAEL of cumulative Cd-A and least-squares cumulative Cd-B was 691 yrs μg/m3 and 8586 months nmol/L, respectively. Among various models for dose–response relationships, a probit model was adopted as the best fitting model. The obtained BMDLs of cumulative Cd-A were 272.3 yrs µg/m3 (BMR5%) and 707.5 yrs µg/m3 (BMR10%). The BMDLs of mean cumulative Cd-B were 3967.2 months nmol/L (BMR5%) and 7798.1 months nmol/L (BMR10%). The BMDLs of least-squares cumulative Cd-B were 3588.6 months nmol/L (BMR5%) and 8616.3 months nmol/L (BMR10%). Assuming a working period of 40 years, the BMDLs for BMR10% corresponded to 17.7 µg/m3 (Cd-A) and 1.8~2.0 µg/L (Cd-B). Discussion: This study provides new valuable information to enhance the reliability of limit values and thereby make a significant contribution to preventing the health effects of Cd in exposed workers.

Objective To compare mortality in chronic kidney disease (CKD) stages 4 and 5 (estimated glomerular filtration rate <30 mL/min/1.73 m2), peritoneal dialysis, haemodialysis and transplanted patients. Design Population-based cohort study. Setting Swedish national healthcare system. Participants Swedish adult patients with CKD stages 4 and 5 (n=3040; mean age 66 years), peritoneal dialysis (n=725; 60 years), haemodialysis (n=1791; 62 years) and renal transplantation (n=606; 48 years) were identified in Stockholm County clinical quality registers for renal disease between 1999 and 2010. Five general population controls were matched to each patient by age, sex and index year. Exposure CKD status (stage 4 or 5/peritoneal dialysis/haemodialysis/transplanted). Primary outcome All-cause mortality was ascertained from the Swedish Causes of Death Register. Mortality HRs were estimated using Cox regression conditioned on age, sex, diabetes status, education level and index year. Results During 6553 person-years, 766 patients with CKD stages 4 and 5 died (deaths/100 person-years 12, 95% CI 11 to 13) compared with 186 deaths during 1113 person-years in peritoneal dialysis (17, 95% CI 15 to 19), 924 deaths during 3680 person-years in haemodialysis (25, 95% CI 23 to 27) and 53 deaths during 2935 person-years in transplanted patients (1.8, 95% CI 1.4 to 2.4). Against matched general population controls, the mortality HR was 3.6 (95% CI 3.2 to 4.0) for CKD, 5.6 (95% CI 3.5 to 8.9) for transplanted patients, 9.2 (95% CI 6.6 to 12.7) for peritoneal dialysis and 12.6 (95% CI 10.8 to 14.6) for haemodialysis. In direct comparison versus CKD, the mortality HR was 1.7 (95% CI 1.4 to 2.1) for peritoneal dialysis, 2.6 (95% CI 2.3 to 2.9) for haemodialysis and 0.5 (95% CI 0.3 to 0.7) for transplanted patients. Conclusions We did not find support for mortality in CKD to be similar to dialysis mortality. The patients with CKD stages 4 and 5 had considerably lower mortality risk than dialysis patients, and considerably higher risk than transplanted patients and matched general population controls.

Adverse drug effects as a consequence of inappropriate dosage are a common cause of hospitalization among the elderly. Older individuals are at a particular risk of overdosing because their kidney function decreases with advancing age and the elderly are often prescribed several pharmaceutical drugs. In addition, serum creatinine levels decrease owing to a reduction in muscle mass with age. Therefore, drug dosing based on the serum creatinine level only, instead of using assessment of the renal function, may result in overdosing of frail elderly patients. Renal function, i.e., the glomerular filtration rate can, with simple formulas, be estimated from analysis of creatinine and/or plasma cystatin C (eGFR). Such estimations performed with modern and validated formulas, as a rule present renal function normalized to the body surface area (mL/min/1.73 m 2 ). A good estimation of how much the normal dosing interval should be prolonged, or the dose reduced, to obtain a desired plasma concentration of drugs that are mainly eliminated by glomerular filtration can be obtained by calculating the ratio between the patient’s eGFR and the normal renal function (about 90–125 mL/min/1.73 m 2 ). Increased knowledge and use of eGFR by prescribing physicians will reduce the risk of overdosing drugs in the elderly.

Long-term exposure to cadmium may cause kidney and bone damage. Urinary cadmium is commonly used as the dose estimate for the body burden of cadmium. However, elevated levels of cadmium in the urine may reflect not only high levels of cadmium dose but also renal dysfunction. In this study we used blood cadmium as the dose estimate. In addition, we analyzed blood lead. We examined 479 men and 542 women, ages 16-81 years, who were environmentally or occupationally exposed to cadmium and lead. We used urinary protein α1-microglobulin as a marker for tubular proteinuria and measured forearm bone mineral density using dual-energy X-ray absorptiometry. The relationship between blood cadmium and tubular proteinuria was strong, even when we excluded occupationally exposed participants. The subgroup with the highest blood cadmium levels had a 4-fold risk of tubular proteinuria compared to the subgroup with the lowest blood cadmium levels. In the older age group (age > 60), the risk of low bone mineral density (z-score < -1) for the subgroup with the highest blood cadmium levels was almost 3-fold compared to the group with lowest blood cadmium levels. We found no similar associations for lead. The observed effects may be caused by higher cadmium exposure in the past. This study strengthens previous evidence that cadmium exposure may affect both bone mineral density and kidney function.

OBJECTIVES To study the dose-response relation between cadmium dose and renal tubular damage in a population of workers and people environmentally or occupationally exposed to low concentrations of cadmium. METHODS Early kidney damage in 1021 people, occupationally or environmentally exposed to cadmium, was assessed from cadmium in urine to estimate dose, and protein HC (α1-microglobulin) in urine to assess tubular proteinuria. RESULTS There was an age and sex adjusted correlation between cadmium in urine and urinary protein HC. The prevalence of tubular proteinuria ranged from 5% among unexposed people to 50% in the most exposed group. The corresponding prevalence odds ratio was 6.0 (95% confidence interval (95% CI) 1.6 to 22) for the highest exposure group, adjusted for age and sex. Multiple logistic regression analysis showed an increasing prevalence of tubular proteinuria with urinary cadmium as well as with age. After adjustment to the mean age of the study population (53 years), the results show an increased prevalence of 10% tubular proteinuria (taking into account a background prevalence of 5%) at a urinary cadmium concentration of 1.0 nmol/mmol creatinine. CONCLUSION Renal tubular damage due to exposure to cadmium develops at lower levels of cadmium body burden than previously anticipated.

ObjectiveTo compare healthcare costs in chronic kidney disease (CKD) stage 4 or 5 not on dialysis (estimated glomerular filtration rate <30 mL/min/1.73m2), peritoneal dialysis, haemodialysis and in transplanted patients with matched general population comparators.DesignPopulation-based cohort study.SettingSwedish national healthcare system.ParticipantsPrevalent adult patients with CKD 4 or 5 (n=1046, mean age 68 years), on peritoneal dialysis (n=101; 64 years), on haemodialysis (n=460; 65 years) and with renal transplants (n=825; 52 years) were identified in Stockholm County clinical quality registers for renal disease on 1 January 2010. 5 general population comparators from the same county were matched to each patient by age, sex and index year.Primary and secondary outcome measuresAnnual healthcare costs in 2009 incurred through inpatient and hospital-based outpatient care and dispensed prescription drugs ascertained from nationwide healthcare registers. Secondary outcomes were annual number of hospital days and outpatient care visits.ResultsPatients on haemodialysis had the highest mean annual cost (€87 600), which was 1.49 (95% CI 1.38 to 1.60) times that observed in peritoneal dialysis (€58 600). The mean annual cost was considerably lower in transplanted patients (€15 500) and in the CKD group (€9600). In patients on haemodialysis, outpatient care costs made up more than two-thirds (€62 500) of the total, while costs related to fluids ($29 900) was the largest cost component in patients on peritoneal dialysis (51%). Compared with their matched general population comparators, the mean annual cost (95% CI) in patients on haemodialysis, peritoneal dialysis, transplanted patients and patients with CKD was 45 (39 to 51), 29 (22 to 37), 11 (10 to 13) and 4.0 (3.6 to 4.5) times higher, respectively.ConclusionsThe mean annual costs were ∼50% higher in patients on haemodialysis than in those on peritoneal dialysis. Compared with the general population, costs were substantially elevated in all groups, from 4-fold in patients with CKD to 11, 29 and 45 times higher in transplanted patients and patients on peritoneal dialysis and haemodialysis, respectively.

Introduction Little is known about the comparative effects of sodium glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), or dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of acute kidney injury (AKI) in routine care, which may differ from the controlled setting of trials. Methods Observational study comparing risks of AKI among new users of SGLT2i, GLP1-RA or DPP-4i in the region of Stockholm, Sweden, during 2008–2018. AKI was defined by ICD-10 codes and creatinine-based KDIGO criteria. We used inverse probability of treatment weighting (IPTW) to adjust for 60 potential confounders, weighted Kaplan–Meier curves and Cox regression to estimate hazard ratios and absolute risks. Results We included 17,407 participants who newly initiated DPP-4i ( N  = 10,605), GLP1-RA ( N  = 4448) or SGLT2i ( N  = 2354). Mean age was 63 years (39% women) and median (IQR) eGFR was 89 (73–100) ml/min/1.73 m 2 . During a median follow-up of 2.5 years, 1411 participants experienced AKI. SGLT2i users had the lowest incidence rate of AKI, 18.3 [CI 95% 14.1–23.4] per 1000 person years, followed by GLP1-RA (22.5; 19.9–25.3) and DPP-4i (26.6; 25–28.2). The weighted 3-year absolute risk for AKI was 5.79% [3.63–8.52] in the SGLT2i group, compared with 7.03% [5.69–8.69] and 7.00% [6.43–7.58] in the GLP1-RA and DPP-4i groups, respectively. The adjusted hazard ratio was 0.73 [CI 95% 0.45–1.16] for SGLT2i vs. DPP-4i, and 0.98 [CI 95% 0.82–1.18] for GLP1-RA vs. DPP-4i. Conclusion This study of routine care patients initiating novel glucose-lowering drugs showed similar occurrence of AKI between therapies, and suggests lower risk for SGLT2i.

Disturbances in calcium metabolism are common in individuals with chronic kidney disease (CKD), but whether they are associated with subsequent kidney function decline is less clear. In a CKD 3–5 cohort of 15,755 adult citizens of Stockholm with creatinine tests taken during 2006–2011 and concurrent calcium testing at cohort entry, we investigated the association between baseline serum calcium and the subsequent change in estimated glomerular filtration rate (eGFR, by CKD-EPI) decline using linear mixed models. Mean (SD) baseline corrected serum calcium was 9.6 (0.5) mg/dL. Mean (95%-confidence interval [CI]) eGFR decline was −0.82 (−0.90; −0.74) mL/min/1.73 m 2 /year. In advanced CKD stages, higher baseline serum calcium was associated with less rapid kidney function decline. The adjusted change (95%-CI) in eGFR decline associated with each mg/dL increase in baseline serum calcium was −0.10 (−0.28; 0.26), 0.39 (0.07; 0.71), 0.34 (−0.02; 0.70) and 0.68 (0.36; 1.00) mL/min/1.73 m 2 /year for individuals in CKD stage 3a, 3b, 4, and 5, respectively. In a subgroup of patients using vitamin D supplements, the association between baseline serum calcium and CKD progression was eliminated, especially in CKD stage 3b and 4. To conclude, in individuals with CKD stage 3b to 5, lower baseline corrected serum calcium, rather than higher baseline serum calcium, associated with a more rapid CKD progression. Lower serum corrected calcium seems to be indicative for vitamin D deficiency.