How Genetics Can Improve Clinical Practice in Chronic Kidney Disease: From Bench to Bedside.

Chronic kidney disease (CKD) is considered a major global health problem with high socio-economic costs: the risk of CKD in individuals with an affected first degree relative has been found to be three times higher than in the general population. Genetic factors are known to be involved in CKD pathogenesis, both due to the possible presence of monogenic pathologies as causes of CKD, and to the role of numerous gene variants in determining susceptibility to the development of CKD. The genetic study of CKD patients can represent a useful tool in the hands of the clinician; not only in the diagnostic and prognostic field, but potentially also in guiding therapeutic choices and in designing clinical trials. In this review we discuss the various aspects of the role of genetic analysis on clinical management of patients with CKD with a focus on clinical applications. Several topics are discussed in an effort to provide useful information for daily clinical practice: definition of susceptibility to the development of CKD, identification of unrecognized monogenic diseases, reclassification of the etiological diagnosis, role of pharmacogenetics.

Chronic Kidney Disease of Undetermined Etiology around the World.

BACKGROUND: Epidemics of chronic kidney disease of uncertain etiology (CKDu) are occurring on the Pacific coast of Central America, in Sri Lankan and Indian agricultural communities, and in other hotspots around the world. CKDu primarily affects male agricultural workers, and traditional risk factors such as diabetes and hypertension are not involved in the pathogenesis. Although a causal factor has not yet been identified, culprits include repeated volume depletion-induced kidney injury, as well as exposure to agrichemicals, heavy metals and nephrotoxins contained in drugs, beverages, and traditional medications. Multiple risk factors may interact in a synergistic fashion thus resulting in chronic kidney damage. The absence of undefined protective factors may amplify the risk. SUMMARY: This review focuses on the current understanding of CKDu by analyzing epidemiology, potential risk factors, and clinical and pathological features as well as geographical peculiarities of each disease. We also focus our attention on the etiology of these conditions in which multiple factors may synergistically contribute to the development and progression of the disease. The last part of the manuscript is dedicated to the research agenda and practical recommendations. Key Messages: Since renal replacement therapy is not extensively available in areas where CKDu is widespread, prevention by avoiding all known potential risk factors is crucial. Innovative healthcare solutions and social policies in endemic areas along with collaborative clinical research projects are needed to better identify factors involved in disease promotion and progression.

Kidney size in relation to ageing, gender, renal function, birthweight and chronic kidney disease risk factors in a general population.

BACKGROUND: The relationship of kidney size to ageing, kidney function and kidney disease risk factors is not fully understood. METHODS: Ultrasound length and parenchymal kidney volume were determined from a population-based sample of 3972 Sardinians (age range 18-100 years). We then identified the subset of 2256 'healthy' subjects to define age- and sex-specific reference ranges (2.5-97.5 percentile) of kidney volume. Logistic regression (accounting for family clustering) was used to identify the clinical characteristics associated with abnormally large kidneys or abnormally small kidneys. RESULTS: In the healthy subset, kidney volume and length increased up to the fourth to fifth decade of life followed by a progressive decrease in men, whereas there was a gradual kidney volume decrease throughout the lifespan of women. In the whole sample, independent predictors of lower kidney volume (<2.5 percentile for age and sex) were male sex, low body mass index, short height, low waist:hip ratio and high serum creatinine (SCr); the independent predictors of larger kidney volume (>97.5 percentile for age and sex) were younger age, female sex, diabetes, obesity, high height, high waist:hip ratio and lower SCr. Estimated heritability for kidney volume was 15%, and for length 27%; kidney volume correlated strongly with birthweight. CONCLUSIONS: Overall, in a general healthy population, kidney measures declined with age differently in men and women. The determinants of kidney parenchymal volume include genetic factors and modifiable clinical factors.

Circulating antithyroid antibodies contribute to the decrease of glomerular filtration rate in lithium-treated patients: a longitudinal study.

BACKGROUND: Concerns about the adverse effects of long-term treatment with lithium include reduced renal function. In the present study, we examined comorbidities which may be associated with chronic kidney disease in a cohort of patients treated with lithium for up to 41 years. METHODS: We studied 394 patients who were treated with lithium for ≥ 5 years. The potential role of comorbidities (diabetes, concurrent antihypertensive medication, treatment with L-thyroxine, and presence of antithyroid peroxidase/microsomes, anti-thyroglobulin, and/or anti-thyrotropin-receptor antibodies) was analysed. We focused on the categories of patients with an estimated glomerular filtration rate (eGFR) lower than 60 or 45 mL/min/1.73 m2 as calculated from serum creatinine according to the Modification of Diet in Renal Disease Study Group. We applied multivariate regression analysis and Cox survival analysis to study the effects exerted by sex, age, duration of lithium treatment, and comorbidities using eGFR categories as the dependent variable. Kaplan-Meier curves were generated to measure the time to decline to an eGFR lower than 45 mL/min/1.73 m2 in patients with positive or negative thyroid antibodies. RESULTS: Age was associated with a decline to an eGFR lower than 60 mL/min/1.73 m2 after controlling for sex, duration of lithium treatment, and comorbidities. Circulating thyroid antibodies were associated with a decline to an eGFR lower than 45 mL/min/1.73 m2. CONCLUSIONS: The present study is the first to suggest a potential role of circulating thyroid antibodies in the severe decline of eGFR in lithium-treated patients.

Genome-Wide Analysis Studies and Chronic Kidney Disease.

In recent years, the very high worldwide prevalence of chronic kidney disease (CKD) has led some authors to talk of an "epidemic." The progression of CKD varies considerably among individuals despite similar aetiologies, optimal blood pressure, and glycaemic control. Over the last decade, through genome-wide association studies (GWAS), more than 50 genetic loci have been identified in association with CKD. Understanding the genetic basis of CKD could provide a better knowledge of the biology of the involved pathways, thus potentially leading to novel tools for the diagnosis, prevention, and therapy of CKD. In this review, we will analyse the role of GWAS in the study of CKD.

Glomerular diseases and cancer: evaluation of underlying malignancy.

Onconephrology is an emerging medical subspecialty focused on the numerous interconnections between cancer and kidney diseases. Patient with malignancies commonly experience kidney problems including acute kidney injury, tumor lysis syndrome, fluid and electrolyte disorders and chronic kidney disease, often as a consequence of the anti-cancer treatment. Conversely, a number of glomerulopathies, tubulopathies and vascular renal diseases can early signal the presence of an underlying cancer. Furthermore, the administration of immunosuppressive drugs, especially cytotoxic drugs and calcineurin inhibitors, may strongly impair the immune response increasing the risk of cancer. The objective of this review article is to: (i) discuss paraneoplastic glomerular disease, (ii) review cancer as an adverse effect of immunosuppressive agents used to treat glomerulopathies, and (iii) in the absence of international approved guidelines, propose a screening program based on expert opinion aimed at guiding nephrologists to early detect malignancies during their clinical practice.

Renal function during long-term lithium treatment: a cross-sectional and longitudinal study.

BACKGROUND: The effects of lithium treatment on renal function have been previously shown, albeit with discrepancies regarding their relevance. In this study, we examined glomerular filtration rate in patients treated with lithium for up to 33 years. METHODS: All lithium patients registered from 1980 to 2012 at a Lithium Clinic were screened. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine concentration using the Modification of Diet in Renal Disease Study Group equation. A cross-sectional evaluation of the last available eGFR of 953 patients was carried out using multivariate regression analysis for gender, current age, and duration of lithium treatment. Survival analysis was subsequently applied to calculate the time on lithium needed to enter the eGFR ranges 45 to 59 mL/min/1.73 m² (G3a) or 30 to 44 mL/min/1.73 m² (G3b). Finally, 4-year follow-up of eGFR was examined in subgroups of patients who, after reduction to an eGFR lower than 45 mL/min/1.73 m² either i) continued lithium at the same therapeutic range or ii) discontinued lithium or continued at concentrations below the therapeutic range (0.5 mmol/L). RESULTS: In the cross-sectional evaluation, eGFR was found to be lower in women (by 3.47 mL/min/1.73 m²), in older patients (0.73 mL/min/1.73 m² per year of age), and in patients with longer lithium treatment (0.73 mL/min/1.73 m² per year). Half of the patients treated for longer than 20 years had an eGFR lower than 60 mL/min/1.73 m². The median time on lithium taken to enter G3a or G3b was 25 years (95% CI, 23.2-26.9) and 31 years (95% CI, 26.6-35.4), respectively. Progression of renal failure throughout the 4-year follow-up after a reduction to an eGFR lower than 45 mL/min/1.73 m² did not differ between the subgroup who continued lithium as before and the subgroup who either discontinued lithium or continued at concentrations below the therapeutic range. CONCLUSIONS: Duration of lithium treatment is to be added to advancing age as a risk factor for reduced glomerular filtration rate. However, renal dysfunction tends to appear after decades of treatment and to progress slowly and irrespective of lithium continuation.

[A postgraduate experience at the ASN's annual meeting]. / L'esperienza di uno specializzando al convegno della Società Americana di Nefrologia.

The annual meeting of the American Society of Nephrology (ASN) is one of the most important conferences in this field. It has a high scientific quality and it receives thousands of participants from all over the world. In this paper, a fellow in Nephrology describes her attendance to this meeting. Moreover, two topics have been selected and summarized: the role of complement in the thrombotic microangiopathy and the autosomal dominant polycystic kidney disease.

Prevalence of CKD and its relationship to eGFR-related genetic loci and clinical risk factors in the SardiNIA study cohort.

The prevalence of CKD and of renal failure vary worldwide, yet parallel increases in leading risk factors explain only part of the differential prevalence. We measured CKD prevalence and eGFR, and their relationship with traditional and additional risk factors, in a Sardinian founder population cohort. The eGFR was calculated using equations from the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease studies. With use of the Kidney Disease Improving Global Outcomes guidelines, a cross-sectional analysis of 4842 individuals showed that CKD prevalence was 15.1%, including 3.6% of patients in the high-risk and 0.46% in the very-high-risk categories. Longitudinal analyses performed on 4074 of these individuals who completed three visits with an average follow-up of 7 years revealed that, consistent with other populations, average eGFR slope was -0.79 ml/min per 1.73 m(2) per year, but 11.4% of the participants had an eGFR decline >2.3 ml/min per 1.73 m(2) per year (fast decline). A genetic score was generated from 13 reported eGFR- and CKD-related loci, and univariable and multivariable analyses were applied to assess the relationship between clinical, ultrasonographic, and genetic variables with three outcomes: CKD, change in eGFR, and fast eGFR decline. Genetic risk score, older age, and female sex independently correlated with each outcome. Diabetes was associated with CKD prevalence, whereas hypertension and hyperuricemia correlated more strongly with fast eGFR decline. Diabetes, hypertension, hyperuricemia, and high baseline eGFR were associated with a decline of eGFR. Along with differential health practices, population variations in this spectrum of risk factors probably contributes to the variable CKD prevalence worldwide.

Mycophenolate mofetil as steroid-sparing treatment for elderly patients with giant cell arteritis: report of three cases.

BACKGROUND AND AIMS: Glucocorticoids have never been studied in a placebo-controlled manner in giant cell arteritis (GCA), but their effectiveness is well established. However, evidence for the efficacy of immunosuppressant drugs as steroid-sparing agents in this disease is highly desirable, especially in elderly patients. We report the use of mycophenolate mofetil (MMF) as a steroid-sparing agent in three patients (mean age 78 years) with GCA, at high risk of longterm high dose glucocorticoids because of type II diabetes mellitus, obesity, hypertension or osteoporosis. METHODS: clinical monitoring and assessment of laboratory parameters were carried out weekly (first month) and then patients were seen in the clinic every 2 weeks. Vascular lesions were also monitored at the onset and during the follow-up by Doppler ultrasonography (every 3 months). RESULTS: all three patients showed clinical benefit, and were also able to taper steroid use to a more rapid regimen compared with the recently suggested steroid reduction approach. MMF was well tolerated, and no signs of toxicity were observed in a mean of 21.6 months (12-29) of follow-up. CONCLUSION: mycophenolate mofetil may be considered a steroid-sparing agent in elderly patients with GCA but, before results of controlled trials become available, MMF may be considered only for patients who do not improve or stabilize with conventional therapy, or in patients for whom reduced steroid dosage is highly recommended.

Long-term effects of methylprednisolone pulses and mycophenolate mofetil in IgA nephropathy patients at risk of progression.

BACKGROUND: IgA nephropathy (IgAN) is a microcosm of glomerular lesions. Some histologic lesions are irreversible and progress toward obliteration of glomerular capillaries. Others are acute inflammatory processes potentially susceptible to reversal by means of immunosuppressive therapies. METHODS: The effects of a combined schedule of steroids and mycophenolate mofetil (MMF) was prospectively examined in a subset of IgAN patients with acute inflammatory histologic changes associated with proteinuria (mean 2,400 mg/day, range 1,130-5,250), hematuria (76 red cells per high-power microscopic field, range 30-100) and renal failure (serum creatinine 1.6 mg/dL, range 1.2-2.9). Patients had diffuse mesangial proliferation with at least 10% florid crescents, mild to moderate degrees of glomerular sclerosis and interstitial changes, and both mesangial and capillary deposition of immunoreactants at immunofluorescence. Treatment consisted of 3 pulses of methylprednisolone (15 mg/kg) followed by oral prednisone (0.8 mg/kg body weight, tapered until discontinuation within 4 months) and MMF 2 g for 6 months. RESULTS: Serum creatinine, proteinuria and microscopic hematuria significantly dropped at 6 months compared with baseline values (p=0.01) and remained lower at the end of follow-up 51 months (range 24-90) later (p<0.01, for proteinuria and hematuria; p=0.08, for serum creatinine). CONCLUSION: Therapy with steroids and MMF may be considered in a subset of IgAN patients with florid glomerular changes, functional impairment and major urinary abnormalities, to prevent subsequent progression toward renal failure.