Lead nephropathy and lead-related nephrotoxicity

INTRODUCTION — Lead exposure can affect a variety of organ systems. The impact of lead exposure on the kidney will be reviewed here. Other clinical manifestations of lead toxicity, as well as the evaluation and management of lead poisoning in adults and children, are discussed separately:

●(See "Lead exposure, toxicity, and poisoning in adults".)

●(See "Childhood lead poisoning: Clinical manifestations and diagnosis".)

●(See "Childhood lead poisoning: Management".)

GENERAL PRINCIPLES

Lead nephropathy versus lead-related nephrotoxicity — The effect of lead exposure on the kidney varies by dose and duration. Lead nephropathy is a type of progressive chronic kidney disease (CKD) caused by high levels of chronic lead exposure. A proximal tubulopathy/Fanconi syndrome may occur as a result of acute, severe lead poisoning and generally resolves with treatment (see 'Pathology' below and 'Clinical manifestations' below). By contrast, lead-related nephrotoxicity refers to lower levels of long-term lead exposure that may contribute to the progression of CKD, regardless of CKD cause.

Features that distinguish between lead nephropathy and lead-related nephrotoxicity are outlined further below:

●Lead nephropathy – Lead nephropathy is characterized histologically by chronic interstitial nephritis, and is a potential complication of prolonged (ie, ≥5 years) high-level lead exposure (ie, blood lead levels persistently >60 mcg/dL [2.9 micromol/L]) [1-5]. The high level of lead exposure required to cause lead nephropathy is now rare in resource-rich countries due to occupational controls and removal of lead from paint, gasoline, and other environmental sources (figure 1). Patients with lead nephropathy often have extrarenal manifestations of lead toxicity. (See 'Lead nephropathy' below.)

●Lead-related nephrotoxicity – Lead-related nephrotoxicity refers to lead exposure as a modifiable risk factor for the progression of CKD, and occurs at low levels of chronic exposure that may still be encountered in resource-rich countries [6]. In this context, lead is typically unrelated to the initial cause of kidney dysfunction, and acts as a secondary factor that accelerates CKD progression (see "Secondary factors and progression of chronic kidney disease"). Patients with lead-related nephrotoxicity generally do not have extrarenal manifestations of lead poisoning. (See 'Lead-related nephrotoxicity' below.)

Measurement of lead dose — For patients who have signs or symptoms of lead poisoning, blood lead levels are the primary way of measuring lead exposure and are used to guide management (see "Lead exposure, toxicity, and poisoning in adults"). The major limitation of blood lead levels is that they do not accurately assess cumulative, long-term lead exposure; blood lead is a short-term measurement with a half-life of approximately 30 days that reflects both exposure from current exogenous sources and the release of endogenous lead from bone and soft-tissue stores [7,8].

Because of this limitation, diagnostic lead chelation can be used to assess the lead body burden in select patients with suspected lead nephropathy. Diagnostic chelation consists of measuring the amount of lead excreted in a timed urine collection after administration of calcium ethylenediaminetetraacetic acid (EDTA). (See 'Making the diagnosis' below.)

Other tests to assess cumulative lead exposure, such as radiograph fluorescence measurements of bone lead, are primarily used in research settings. (See "Lead exposure, toxicity, and poisoning in adults", section on 'Additional testing'.)

SOURCES OF LEAD EXPOSURE — There are a number of current sources of lead exposure, which are primarily related to occupational exposures in adults and to ingestion or inhalation of environmental lead in adults and children (table 1). In addition, since lead accumulates in bone, the body lead burden from past exposures also contributes to current exposure.

Exposure sources are discussed in detail elsewhere. (See "Lead exposure, toxicity, and poisoning in adults", section on 'Sources of exposure' and "Childhood lead poisoning: Exposure and prevention", section on 'Exposure'.)

LEAD NEPHROPATHY — Lead nephropathy is increasingly rare, particularly in resource-rich countries where lead exposure has been reduced through occupational and environmental controls.

Pathology — The kidney pathology associated with high levels of lead exposure depends on whether the exposure is acute or chronic.

●Acute high-level lead poisoning (ie, blood lead level >100 mcg/dL) initially injures the proximal tubules in association with intranuclear inclusion bodies composed of a lead-protein complex [9]. Proximal tubular injury may lead to diminished reabsorption and to the Fanconi syndrome. (See 'Fanconi syndrome' below.)

●Chronic high-level lead exposure, at blood levels >60 mcg/dL, can cause a chronic interstitial nephritis that leads to a persistent and progressive reduction in the glomerular filtration rate (GFR; ie, chronic kidney disease [CKD]). Kidney biopsy findings are nonspecific and include tubular atrophy, interstitial fibrosis, low-level inflammatory cell infiltrates, hypertrophic arteriolar changes, and variable degrees of glomerular scarring [1,10,11]. In this setting, proximal tubular intranuclear inclusion bodies are often absent [9,11].

Clinical manifestations

Fanconi syndrome — Signs of a Fanconi-type syndrome, such as glucosuria, aminoaciduria, and phosphaturia, have been observed in patients (generally children) with acute, severe lead poisoning [11]. The Fanconi syndrome generally resolves with treatment of acute lead poisoning and is not a typical feature of lead-mediated CKD. However, in affected patients glucosuria and aminoaciduria may persist for a prolonged period [12].

Chronic kidney disease — CKD due to prolonged high-level lead exposure is often accompanied by extrarenal manifestations of lead toxicity, especially hypertension and gout. (See "Lead exposure, toxicity, and poisoning in adults", section on 'Clinical manifestations' and "Childhood lead poisoning: Clinical manifestations and diagnosis".)

Patients with lead nephropathy typically present with the following:

●A persistent and slowly progressive reduction in the estimated GFR (eGFR)

●Hypertension

●Hyperuricemia; a history of gout is frequently obtained [3,5,11]

●A benign urinalysis, with the sediment revealing few if any cells or casts, and minimal or only mildly elevated urinary protein excretion (eg, ≤1 g/day)

These features are not specific, and lead nephropathy may be confused with other causes of CKD. (See 'Differential diagnosis' below.)

Diagnosis

When to suspect lead nephropathy — Lead nephropathy should be suspected in patients who present with the triad of CKD, hypertension, and gout, or in patients with CKD who have evidence of lead poisoning in other organ systems. (See "Lead exposure, toxicity, and poisoning in adults" and "Childhood lead poisoning: Clinical manifestations and diagnosis".)

Evaluation — For patients with suspected lead nephropathy, we obtain a history to determine potential current or past sources of lead exposure, as well as the cumulative duration of any exposure(s). A patient-administered questionnaire (figure 2) is a useful tool to identify the need to explore specific lead sources in greater detail (table 1). (See "Lead exposure, toxicity, and poisoning in adults", section on 'Sources of exposure' and "Childhood lead poisoning: Exposure and prevention", section on 'Exposure'.)

Patients without a history of current or past lead exposure do not require further evaluation for lead nephropathy. Patients with a history of potential or definitive lead exposure and CKD should undergo the following:

●A thorough evaluation for other causes of CKD, since many patients with lead exposure do not have lead nephropathy. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)

●Assessment for the extrarenal signs and symptoms of lead poisoning. Extrarenal manifestations of lead exposure suggest lead nephropathy as a cause of CKD. (See "Lead exposure, toxicity, and poisoning in adults", section on 'Clinical manifestations'.)

●Measurement of blood lead levels. Because blood lead levels may be less elevated if high-level lead exposure has declined or stopped, we also make every effort to obtain the results of any previous blood lead tests. Workers in many occupations associated with lead exposure are mandated to undergo periodic blood testing for lead. (See "Lead exposure, toxicity, and poisoning in adults", section on 'OSHA and other governmental lead regulations'.)

Making the diagnosis — There is no definitive test for lead nephropathy, and generally accepted or validated clinical criteria to make the diagnosis do not exist.

We make the diagnosis of lead nephropathy in patients who meet all three of the following criteria:

●A history of lead exposure with a cumulative duration ≥5 years. (See 'Evaluation' above.)

●Exclusion of alternative causes of CKD, as suggested by features such as an abnormal urinalysis, proteinuria >1 g/day, a paraprotein, or use of a nephrotoxic drug. In patients who are candidates for chelation-based treatment of lead nephropathy (see 'Chelation in select patients' below), we obtain a kidney biopsy. Although primarily done to assess prognosis and chronicity, kidney biopsy in this setting also allows for the definitive exclusion of other causes of CKD.

●Laboratory evidence of high-level, chronic lead exposure. Although multiple blood lead levels >60 mcg/dL over the course of at least five years are sufficient laboratory evidence of high-level, chronic lead exposure, such data are rarely available (see 'Measurement of lead dose' above). In patients who are candidates for chelation-based treatment of lead nephropathy (see 'Chelation in select patients' below), diagnostic chelation may be used to assess chronic lead exposure. Consistent with the original studies describing lead nephropathy, we consider a urinary lead excretion >600 mcg (2.9 micromol) in the 72 hours after one gram of intravenous calcium ethylenediaminetetraacetic acid (EDTA; administered over one to two hours) to indicate a lead body burden capable of causing lead nephropathy.

Patients with CKD and a history of lead exposure who do not meet the strict criteria above for lead nephropathy are considered instead to have lead-related nephrotoxicity. (See 'Lead nephropathy versus lead-related nephrotoxicity' above and 'Lead-related nephrotoxicity' below.)

The diagnosis of lead poisoning in both adults and children is discussed in detail elsewhere. (See "Lead exposure, toxicity, and poisoning in adults", section on 'Evaluation' and "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Evaluation'.)

Differential diagnosis — Like lead nephropathy, a variety of CKD etiologies are characterized by a bland urine sediment, minimal proteinuria, and variable degrees of hypertension and/or hyperuricemia:

●Hypertensive nephrosclerosis results from poorly controlled chronic hypertension. In some patients, the only feature distinguishing lead nephropathy from hypertensive nephrosclerosis is the presence of prolonged, high-level lead exposure. (See "Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis".)

●Ischemic nephropathy is CKD due to atherosclerotic renal artery stenosis. These patients are likely to have a history of severe or refractory hypertension, an acute elevation in blood pressure over a previously stable baseline, or relatively rapid deterioration of kidney function in the setting of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy. Patients with ischemic nephropathy frequently have atherosclerosis in other vascular beds, including coronary artery disease or peripheral arterial disease. (See "Chronic kidney disease resulting from atherosclerotic renal artery stenosis".)

●Chronic urate nephropathy is a form of CKD induced by the deposition of urate crystals in the medullary interstitium and is rare in the absence of tophaceous gout. A definitive diagnosis is generally made by kidney biopsy. (See "Uric acid kidney diseases".)

●Uromodulin kidney disease is an autosomal dominant tubulointerstitial kidney disease caused by a heritable mutation of the uromodulin (UMOD) gene. It is characterized by hyperuricemia and gout early in the course of the disease and by progressive kidney dysfunction. (See "Autosomal dominant tubulointerstitial kidney disease", section on 'ADTKD due to UMOD pathogenic variants'.)

Careful evaluation of patients considered to have hypertensive nephrosclerosis or chronic urate nephropathy in selected studies performed in the 1980s revealed that many actually had lead nephropathy [13-15]. However, the applicability of these findings to current practice is uncertain since the high-level lead exposure required to cause lead nephropathy is increasingly rare, at least in resource-rich countries.

Treatment — Patients with lead nephropathy should receive the same general care directed at slowing CKD progression as patients with CKD from other causes (see "Overview of the management of chronic kidney disease in adults"). Lead-specific treatment is discussed below.

Minimize lead exposure — The mainstay of treatment is to avoid further exogenous lead exposure (table 1). Blood lead levels determine the necessity of, and schedule for, ongoing blood lead level monitoring as well as other interventions necessary to reduce lead exposure. Except for lower thresholds for referral to a specialist in occupational and environmental medicine, blood lead level-based management to reduce lead exposure for patients with CKD is similar to that for lead exposed patients in the general population. (See "Lead exposure, toxicity, and poisoning in adults", section on 'Initial management' and "Childhood lead poisoning: Management".)

We advocate lower thresholds for specialty referral in patients with CKD because of the potentially adverse effects of even low-level lead exposure on CKD progression. We advise referral to a clinician with expertise in occupational and environmental medicine or medical toxicology for patients with CKD who have one or both of the following:

●Blood lead levels >5 mcg/dL on two measurements obtained at least one month apart, despite the removal of identified sources of lead exposure. Patients with a long history of previous exposure and large bone stores of lead may have persistently elevated blood lead levels that decline only slowly, even in the absence of ongoing lead exposure. Specialty care can be useful in such patients by ensuring that all sources of lead have been removed, assisting in various workers' compensation and regulatory issues that arise with occupationally exposed patients, and assessing the need for therapeutic chelation.

●eGFR <60 mL/min/1.73 m² and risk of present or future occupational lead exposure. Lead exposure in such patients should be minimized to levels far below those legally mandated by most states in the United States.

Chelation in select patients

●Chelation criteria – Chelation therapy, based on blood lead levels and symptoms, is clearly indicated for certain patients with lead poisoning. (See "Lead exposure, toxicity, and poisoning in adults", section on 'Chelation therapy'.)

In the absence of such indications, the benefit of chelation therapy for the management of patients with lead nephropathy is uncertain. However, for patients with lead nephropathy who do not have severe and irreversible kidney damage, we suggest chelation therapy provided it can be supervised by an experienced specialist in occupational and environmental medicine and/or a medical toxicologist.

The potential benefits of chelation for lead nephropathy are expected to be greater in patients with less severe CKD (ie, less kidney fibrosis). As such, we only perform chelation for lead nephropathy in patients who have all the following characteristics:

•eGFR ≥30 mL/min/1.73 m², or eGFR ≥20 mL/min/1.73 m² with a decline in eGFR >3 mL/min/1.73 m²/year for at least two years despite optimal CKD care for at least one year

•Kidney size >8 cm on kidney ultrasound

•Interstitial fibrosis <50 percent on kidney biopsy

Our approach to chelation is based on clinical experience; no high-quality data demonstrate that chelation is an effective treatment for lead nephropathy [3,16,17]. One study described the results of chelation therapy in eight lead workers with excessive body lead burdens, defined as urinary lead excretion >1000 mcg (4.8 micromol) in the 24 hours after calcium EDTA chelation, and GFRs <90 mL/min/1.73 m² [3]. Kidney biopsy confirmed the diagnosis of chronic interstitial nephritis, consistent with lead nephropathy, and excluded other causes. The patients were treated with calcium EDTA three times weekly for 6 to 50 months; four had an increase in GFR of ≥20 percent.

●Mechanism of benefit – The mechanism of potential benefit from chelation therapy in patients with lead nephropathy is not well understood. Studies in rodent models of lead nephropathy found that chelation-associated improvement in GFR was not associated with a similar degree of histologic improvement [18,19].

●Adverse effects – A potential adverse effect of chelation therapy is redistribution of lead into the central nervous system, although a reduction in brain lead levels following EDTA chelation has also been reported [20-23]. Mobilization of lead from bone and subsequent excretion via the kidneys is another potential concern; both are greater in patients with lead nephropathy than in patients with CKD in low-lead settings. Only the latter were included in chelation trials that reported beneficial effects on kidney outcomes. (See 'Lead-related nephrotoxicity' below.)

Acute kidney injury was noted in reports from the early 1980s of calcium EDTA therapy given at high doses and, in children, when combined with another chelator [21,24]. Adverse kidney effects were not observed in subsequent studies in adults using lower EDTA doses [21,25-29]. However, published chelation experience in patients with CKD, particularly those with high lead body burdens, is limited.

LEAD-RELATED NEPHROTOXICITY — In patients with underlying chronic kidney disease (CKD) from any cause, lead exposure at the lower levels encountered in resource-rich countries may contribute to the progression of CKD. We refer to this as lead-related nephrotoxicity [6], which is typically not associated with extrarenal manifestations of lead poisoning. (See 'Lead nephropathy versus lead-related nephrotoxicity' above.)

Mechanism — The mechanisms by which even low levels of lead exposure may accelerate the progression of CKD are unclear. However, it is possible that lead exposure may, at least initially, result in glomerular hyperfiltration, which in turn may contribute to kidney injury.

Lead-induced hyperfiltration has been noted in animal models [4]. In humans, evidence of lead-induced hyperfiltration is predominantly circumstantial: observational data report that lead exposure is associated with an initial increase in glomerular filtration rate (GFR), as manifested by a lower serum creatinine concentration and/or a higher creatinine clearance. These findings have been reported in lead workers in South Korea, Belgium, and Taiwan [30-32]; in European children [33]; and in adult survivors of childhood lead poisoning [34]. A study of 53 Polish male steel workers (exposed group) and 40 office workers (control group) reported a positive association between blood lead (geometric mean of 14.6 mcg/dL) and glomerular filtration assessed by renal scintigraphy [35].

In the Korean lead worker study, the associations of higher lead dose with lower serum creatinine and higher creatinine clearance were noted in younger workers, while older workers had the expected association between higher lead dose and higher serum creatinine concentrations [30]. These findings are consistent with initial lead-induced hyperfiltration followed by later lead-induced decline in kidney function.

Surveillance in all patients with CKD stage 3 or greater — We incorporate assessment of lead exposure into the routine care of patients with CKD.

●Assessment of lead exposure – For patients with CKD stage 3 or greater (ie, estimated GFR [eGFR] <60 mL/min/1.73 m²), regardless of etiology, we assess past and current lead exposure at least once by using the provided questionnaire (figure 2) and table (table 1). Patients without a history of lead exposure do not require additional lead-specific evaluation. However, if the questionnaire indicates potential or definitive exposure to lead, past or present, we obtain the following to determine management:

•A history to determine the cumulative duration of any exposure(s).

•A blood lead level measurement.

•The results of any previous blood lead tests.

Rarely, the evaluation above may prompt suspicion for lead nephropathy as a cause of CKD; in such patients, this diagnosis should be pursued and, if confirmed, managed appropriately (see 'Diagnosis' above and 'Treatment' above). Otherwise, we consider patients to have lead-related nephrotoxicity rather than lead nephropathy, and we manage them as such. (See 'Management' below.)

●Supporting evidence – Data demonstrating that identification of potential or definitive low-level lead exposure has benefit for patients with CKD are limited (table 2). However, research in diverse populations, described below, supports the concept of lead-related nephrotoxicity.

•General population studies – In the general population, multiple prospective observational studies provide evidence supporting a link between chronic lead exposure and nephrotoxicity [36-42]. The following studies illustrate the range of findings:

-Among 1434 participants of the Donfeng-Tongji cohort, which included retired automobile manufacturing workers, higher plasma lead levels were associated with more rapid eGFR decline over a mean of 4.6 years [37].

-In a large prospective cohort of 2567 participants with a median baseline blood lead level of 2.5 mcg/dL (0.12 micromol/L) followed for 16 years, those in the highest (median 4.6 mcg/dL; 0.22 micromol/L) as compared with lowest quartile of blood lead levels had an increased risk of developing CKD (adjusted hazard ratio [HR] 1.5, 95% CI 1.1-2.1) [40].

•Studies in patients with CKD – In early studies of lead exposure in patients with CKD, body lead burden, assessed by diagnostic chelation, was high [15,25]. Subsequent studies have examined much lower body lead burdens and/or blood lead levels (table 2) [26-28,43-45]:

-One prospective study evaluated 121 patients with nondiabetic CKD in Taiwan who, at study entry, had a mean serum creatinine of 2.1 mg/dL (186 micromol/L) and a mean eGFR of 36 mL/min/1.73 m² [43]. The patients had no history of exposure to lead and had a normal body lead burden, defined as a 72-hour post-calcium ethylenediaminetetraacetic acid (EDTA) lead excretion <600 mcg (2.9 micromol). The 72-hour post-calcium EDTA lead excretion was between 80 and 599 mcg (0.4 and 2.9 micromol) in 63 patients (high-normal body lead burden) and below 80 mcg (0.4 micromol) in 58 (low-normal body lead burden); mean blood lead levels were 4.9 and 3.4 mcg/dL (0.24 and 0.16 micromol/L), respectively. Kidney function was similar in the two groups at baseline. The primary endpoint of doubling of the serum creatinine or the need for dialysis at four years occurred significantly more often in the patients with high-normal body lead burden (23.8 versus 3.4 percent). In addition, each 1 mcg/dL (0.05 micromol/L) higher blood lead level at baseline was associated with a 4 mL/min/1.73 m² lower eGFR.

-In a population-based, nested, case-control study of 118 participants with end-stage kidney disease (ESKD) and 378 controls, elevated erythrocyte lead levels were independently associated with an increased risk of ESKD (adjusted odds ratio 1.01 for each unit increase in erythrocyte lead, 95% CI 1.00-1.02) [39].

-In a study of 670 kidney transplant recipients with median lead level of 3.1 mcg/dL (0.15 micromol/L), a doubling in plasma lead was associated with a 59 percent increased risk of graft failure (HR 1.59, 95% CI 1.14-2.21) at a median of 4.9 years of follow-up [45].

However, some studies in patients with CKD did not find associations between low-level lead exposure and adverse kidney outcomes [46].

•Pediatric studies – Chronic low-level lead exposure may be associated with kidney dysfunction in children.

-Among 769 adolescents aged 12 to 20 years who participated in National Health and Nutrition Examination Survey III (1988 to 1994), higher blood lead levels were associated with lower cystatin-C-based eGFRs; those with lead levels >3 mcg/dL had lower eGFRs compared with those whose levels were <1 mcg/dL [47]. In a model adjusted for age, sex, race/ethnicity, urban versus rural residence, tobacco smoke exposure, obesity, household income, and education, a twofold higher blood lead level was associated with a 2.9 mL/min/1.73 m² lower eGFR. Analyses using creatinine-based equations showed similar associations between blood lead and eGFR, although the associations were not significant. Notably, 99 percent of the study participants had blood lead levels <10 mcg/dL.

-An analysis in 391 participants in the Chronic Kidney Disease in Children prospective cohort study, whose mean blood lead and measured GFR were 1.2 mcg/dL and 44.4 mL/min/1.73 m², respectively, observed an association that was significant only among the 73 children with CKD due to glomerular disease. In this group, each 1 mcg/dL increase in blood lead level was associated with a -12.1 (95% CI -22.2 to -1.9) percent decrease in GFR.

-The impact of prenatal lead exposure was assessed in Bangladeshi children at 4.5 years of age. Blood pressure and eGFR were not associated with maternal erythrocyte lead levels. However, an inverse association between maternal lead and kidney volume, measured by sonography, was observed [48].

-In a study of 453 mother-child pairs, prenatal lead exposure was inversely associated with preadolescent eGFR (ages 8 to 12), but only in children who were overweight [49].

However, not all pediatric studies have reported associations between prolonged low-level lead exposure and decreased kidney function [33].

•Occupational studies – Current occupational lead exposure in resource-abundant countries is usually lower than levels associated with lead nephropathy but higher than environmental exposure in most general population studies. Representative studies include the following:

-A cohort study compared the incidence of ESKD over a median follow-up of 12 years among 58,307 individuals with blood lead levels identified from a blood lead surveillance program conducted by the National Institute for Occupational Safety and Health [50]. ESKD status was determined by matching the cohort against individuals with ESKD identified by the United States Renal Data Systems. Among those followed for more than five years, compared with the United States population, individuals with blood lead concentrations >51 mcg/dL had a greater risk of ESKD (standardized incidence ratio 1.56, 95% CI 1.02-2.29). In an analysis of the 18-year follow-up of this cohort, rates of ESKD were higher among those with higher blood lead levels although the results were not statistically significant [51].

-In 537 current and former Korean lead workers followed over a two-year period, tibia lead and change in blood lead were associated with change in serum creatinine and calculated creatinine clearance [52]. Although participants in this study had serum creatinine levels that decreased on average over the course of the study, the decrease in creatinine was greater in individuals whose blood lead levels decreased over time and in those with lower tibia lead levels.

However, not all occupational studies have reported associations between higher levels of lead exposure and worse kidney function [53].

Management — Patients with lead-related nephrotoxicity should receive the same general care directed at slowing the progression of CKD as patients with CKD who do not have a history of lead exposure (see "Overview of the management of chronic kidney disease in adults"). Lead-specific management is discussed below.

●Minimize lead exposure – For patients with lead-related nephrotoxicity, we take the same blood lead level-based approach to minimize lead exposure as that for patients with lead nephropathy. (See 'Minimize lead exposure' above.)

●Chelation therapy – Provided blood lead levels and symptoms/signs do not indicate lead poisoning (see "Lead exposure, toxicity, and poisoning in adults", section on 'Chelation therapy'), we do not use chelation therapy to treat lead-related nephrotoxicity. There are potential concerns about the safety of chelation related to both redistribution of lead into the central nervous system and toxicity of the chelating agents (see 'Chelation in select patients' above). Of particular relevance for patients with low levels of lead exposure, cognitive impairment has been reported in non-lead-exposed control rats following chelation with succimer [22]. Furthermore, the evidence to support a kidney benefit of chelation in the low-lead setting remains limited. As discussed below, existing clinical trials have been small and were conducted at a single medical center [26-29,54].

A number of chelation trials, all from the same group in Taiwan, have reported efficacy in patients with nondiabetic and diabetic CKD who had no history of exposure to lead [26-29,54]. One of these trials included 64 patients with nondiabetic, progressive CKD who had baseline serum creatinine concentration between 1.5 and 3.9 mg/dL (133 and 345 micromol/L), had high-normal body lead burdens defined by 72-hour post-calcium EDTA lead excretion of 80 to 599 mcg (0.4 to 2.9 micromol), and had been observed for 24 months [26].

The patients were randomly assigned to placebo infusions or weekly calcium EDTA chelation therapy (1 g) for three months, unless 72-hour post-calcium EDTA lead excretion fell below 60 mcg (0.29 micromol). Weekly chelation was repeated over the next two years if there were increases in serum creatinine in association with rebound increases in 72-hour post-calcium EDTA lead excretion. Baseline mean blood lead levels were approximately 6 mcg/dL (0.29 micromol/L) in the treated and control groups. At 27 months, chelation therapy was associated with a slowing or reversal of the progressive decline in GFR compared with placebo (mean change of +2.1 versus -6 mL/min/1.73 m²).

A subsequent randomized trial by the same group demonstrated a similar magnitude of benefit from chelation therapy in CKD patients with the lowest body lead burden studied to date (defined as 72-hour post-calcium EDTA lead excretion between 20 and 79 mcg [0.1 and 0.38 micromol]) [28]. The baseline mean blood lead level in the treated group in this study was 2.6 mcg/dL (0.13 micromol/L).

The potential benefit from chelation therapy in CKD patients with low-level lead exposure raises two mechanistic possibilities, both of which may be involved:

•Lead-related nephrotoxicity contributes to progression in patients with CKD.

•The benefits of chelation therapy may be due to mechanisms other than removal of body lead stores. Consistent with this hypothesis is the observation that chelation therapy with dimercaptosuccinic acid had a beneficial effect on nephrosclerosis in a non-lead-exposed rat model [55].

Before chelation therapy in CKD patients with low-level lead exposure can be recommended, confirmation of efficacy and safety in larger populations at additional centers is required. However, given the size of the potentially affected population, this approach could yield important public health benefits [56].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults" and "Society guideline links: Lead and other heavy metal poisoning".)

SUMMARY AND RECOMMENDATIONS

●General principles – Lead nephropathy is a type of chronic kidney disease (CKD) caused by high levels of long-term lead exposure. By contrast, lead-related nephrotoxicity refers to much lower levels of lead exposure that may contribute to the progression of CKD, regardless of CKD cause. (See 'General principles' above.)

●Sources of lead exposure – There are a number of current sources of lead exposure, which are primarily related to occupational exposures and to ingestion or inhalation of environmental lead (table 1). (See "Lead exposure, toxicity, and poisoning in adults", section on 'Sources of exposure' and "Childhood lead poisoning: Exposure and prevention", section on 'Exposure'.)

●Lead nephropathy – Lead nephropathy is increasingly rare, particularly in resource-rich countries where lead exposure has been reduced through occupational and environmental controls.

•Clinical manifestations – Patients with lead nephropathy typically present with slowly progressive CKD, a relatively normal urine sediment, and minimal or only mildly elevated urinary protein excretion. Extrarenal manifestations of lead toxicity, especially hypertension and gout, are often present. Acute, severe lead poisoning may cause a proximal tubulopathy/Fanconi syndrome that generally resolves with treatment. (See 'Clinical manifestations' above.)

•Diagnosis – We diagnose lead nephropathy based on a history of long-term lead exposure, laboratory evidence of high-level, chronic lead exposure, and exclusion of alternative causes of CKD. (See 'Diagnosis' above.)

•Treatment – Patients with lead nephropathy should receive the same general care directed at slowing the progression of CKD as patients with CKD from other causes. Lead-specific management includes the following:

-Minimize lead exposure – The mainstay of treatment for lead nephropathy is avoidance of further exogenous lead exposure. Blood lead levels determine the specific interventions necessary to reduce lead exposure. (See 'Minimize lead exposure' above.)

-Chelation in select patients – Chelation therapy, based on blood lead levels and symptoms, is clearly indicated for certain patients with lead poisoning (see "Lead exposure, toxicity, and poisoning in adults", section on 'Chelation therapy'). In the absence of such indications, the benefit of chelation therapy for patients with lead nephropathy is uncertain; our approach to chelation in this setting is based on clinical experience rather than high-quality data. For patients with lead nephropathy who do not have severe and irreversible kidney damage, we suggest chelation therapy in addition to general CKD care and avoidance of further lead exposure, rather than general CKD care and avoidance of further lead exposure alone (Grade 2C) (see 'Chelation in select patients' above). If performed, chelation therapy should be provided by an experienced specialist in occupational and environmental medicine or a medical toxicologist.

●Lead-related nephrotoxicity – Patients with lead-related nephrotoxicity typically do not have extrarenal manifestations of lead poisoning.

•Surveillance – Because even low levels of lead exposure are a modifiable risk factor for the progression of CKD, we evaluate all patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² for lead-related nephrotoxicity. The initial step in evaluation is a self-administered questionnaire (figure 2) and a table (table 1) to identify potential sources of past and present lead exposure. (See 'Surveillance in all patients with CKD stage 3 or greater' above.)

•Management – For patients with lead-related nephrotoxicity, we take the same blood lead level-based approach to minimizing lead exposure as that for patients with lead nephropathy. Provided blood lead levels and symptoms do not indicate lead poisoning, we do not chelate patients with lead-related nephrotoxicity. (See 'Management' above.)