Investigating Subtle Kidney Injury in Primary Hyperparathyroidism by Means of Sensitive and Specific Biomarkers

Cristiana Cipriani; Jessica Pepe; Luciano Colangelo; Valeria Fassino; Marco Occhiuto; Piergianni Biondi; Luciano Nieddu; Salvatore Minisola


Clin Endocrinol. 2019;91(5):660-668. 

In This Article

Abstract and Introduction


Objective: Kidney involvement is a common complication in primary hyperparathyroidism (PHPT). No study so far has assessed the prevalence of kidney injury developing before the reduction in glomerular filtration rate (GFR) in PHPT. The study was aimed at establishing the potential role of biomarkers of kidney injury in detecting subtle renal damage in patients with PHPT.

Design: Cross-sectional study.

Patients: A total of 69 postmenopausal patients with PHPT and 41 healthy age- and sex-matched subjects were studied. Exclusion criteria were as follows: GFR < 30 mL/min, chronic inflammatory disease, nephrotic syndrome, infection, malignancy, heart failure, recent exposure to iodinated contrast media or nonsteroidal anti-inflammatory drugs.

Measurements: We measured a panel of sensitive biomarkers of kidney injury in PHPT vs controls.

Results: Mean FGF23 and Klotho were higher in PHPT (72 ± 48 and 811 ± 366 pg/mL, respectively) than controls (53 ± 23.5 and 668.6 ± 17; P < .02 and P < .05). Urine KIM-1/uCr was significantly higher in PHPT (1.4−6 ± 1.3−6) than controls (9.2−7 ± 7−7; P < .05); this was particularly evident in the CrCl 60–89 mL/min category (1.36 ± 97 vs 8.2−7 ± 3.6−7; P < .02). Mean values of urine NGAL/uCr were higher in PHPT with (n = 28) compared to those without kidney stones (n = 35; 1.8−5 ± 1.4−5 and 1−5 ± 8−6; P < .0001). We found significant positive associations between urine NGAL/uCr and Ca (R = .292, P < .02) and urine KIM1/uCr and PTH (R = .329, P < .01).

Conclusions: We propose the utilization of these molecules, particularly urine KIM-1/uCr and urine NGAL/uCr ratios for the assessment of subtle kidney injury in patients with PHPT. These molecules are elevated in tubular necrosis and have potential role in the development of kidney damage in PHPT, according to the severity of the disease.


Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by the hyper function of one or more parathyroid glands and consequent hypercalcemia. The disease is diagnosed on the basis of chronically elevated serum calcium concentration and high or not appropriately suppressed parathyroid hormone (PTH) levels.[1,2] The asymptomatic form is currently the most common clinical presentation of PHPT, but classical target organs, namely the kidneys and the skeleton, remain frequently affected by complications.[3] Kidney stones and mild renal insufficiency, and osteoporosis and fragility fractures are the most frequent complications affecting the two main target organs.[3,4] Parathyroidectomy is recommended in PHPT patients presenting with skeletal and renal complications, as successful surgery has been associated with prevention of worsening and/or improvement of these conditions.[5]

With reference to the renal involvement, patients with PHPT may present nephrolithiasis (the most common complication of the disease), nephrocalcinosis, hypercalciuria and chronic kidney disease (CKD).[3] In particular, an estimated glomerular filtration rate (GFR) <60 mL/min is reported in a figure of 12%-19% depending on series and this value represents the threshold under whom parathyroidectomy is recommended.[6,7] The pathophysiology of CKD in PHPT is not completely understood. The presence of nephrolithiasis or nephrocalcinosis, as well as indices associated with severity of the disease, was not found to be predictors of kidney dysfunction in patients with PHPT.[7,8] Walker et al[8] have reported that traditional risk factors for CKD, as age and diastolic blood pressure, are rather associated with altered renal function in a cohort of 114 patients with mild PHPT.

Assessment of GFR in PHPT has been performed also through the evaluation of cystatin C, a protein with low molecular weight, filtered by the glomerulus and used in the evaluation of renal function as more sensitive than creatinine.[9] Data have shown that 18.4% of PHPT patients with GFR > 60 mL/min have higher cystatin C levels than controls, thus presenting a condition of preclinical CKD that is not captured by the measurement of creatinine levels.[9] Additionally, the Kidney Disease Improving Global Outcomes (KDIGO) definition of CKD includes, besides the altered kidney function, the presence of kidney damage as evaluated by factor other than GFR.[10] Hence, development of kidney damage occurs before the deterioration of kidney function and reduction in GFR values.[10] With the aim of capturing abnormalities preceding the decrease in GFR, novel biomarkers of kidney injury have been developed showing a high sensitivity in detecting the early kidney damage in several conditions.[11,12] Studies in humans mainly focused on the use of markers of kidney injury in different emergency settings, as critically ill patients, heart failure, after major cardiac surgery, kidney transplantation or cisplatin administration, and in the evaluation of contrast-induced acute kidney injury.[11,13] Elevation of many of the novel biomarkers has been described in animal and human studies of drug-induced kidney toxicity [eg kidney injury molecule-1 (KIM-1), β2-microglobulin (B2M), cystatin C, interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin, (NGAL)].[14]

Fewer data are reported in chronic disease.[15,16] The overall data showed that the assessment of a panel of the novel biomarkers is useful in the early detection of kidney injury, with high prognostic value.[11,13] As far as endocrine disease, recent works have shown that the assessment of biomarkers of tubular damage could have diagnostic value in screening patients for diabetic kidney disease.[16] Additionally, animal data have shown a direct association between specific biomarkers, mechanism of renal damage (ischaemic, toxic, inflammatory, etc) and the level of the nephron interested by injury.[12] There has been no study so far assessing the utility of these biomarkers in patients with PHPT.

In this cross-sectional study, we sought to establish the potential role of a panel of sensitive and specific biomarkers of kidney injury in detecting subtle renal damage in patients with PHPT. Correlations with factors associated with severity of the disease will be also made in order to evaluate mechanisms associated with CKD in PHPT.