Association of a Polygenic Risk Score With Osteoporosis in People Living With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether a polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS: Swiss HIV Cohort Study participants of self-reported European descent underwent ≥2 per-protocol dual x-ray absorptiometry (DXA) measurements ≥2 years apart (2011-2020). Univariable and multivariable odds ratios (ORs) for DXA-defined osteoporosis were based on traditional and HIV-related risk factors and a genome-wide PRS built from 9413 single-nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS: We included 438 participants: 149 with osteoporosis and 289 controls (median age, 53 years; 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis PRS (top vs bottom quintile) had univariable and multivariable-adjusted osteoporosis ORs of 4.76 (95% CI, 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture yielded univariable osteoporosis ORs of 2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9). CONCLUSIONS: In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS after adjustment for established risk factors, including exposure to tenofovir disoproxil fumarate.

Rapid Progression of Kidney Dysfunction in People Living With HIV: Use of Polygenic and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Risk Scores.

BACKGROUND: In people with human immunodeficiency virus (PWH), it is unknown whether genetic background associates with rapid progression of kidney dysfunction (ie, estimated glomerular filtration rate [eGFR] decrease of >5mL/min/1.73m2 per year for ≥3 consecutive years). METHODS: We obtained univariable and multivariable hazard ratios (HR) for rapid progression, based on the clinical D:A:D chronic kidney disease (CKD) risk score, antiretroviral exposures, and a polygenic risk score based on 14 769 genome-wide single nucleotide polymorphisms in white Swiss HIV Cohort Study participants. RESULTS: We included 225 participants with rapid progression and 3378 rapid progression-free participants. In multivariable analysis, compared to participants with low D:A:D risk, participants with high risk had rapid progression (HR =  1.82 [95% CI, 1.28-2.60]). Compared to the first (favorable) polygenic risk score quartile, participants in the second, third, and fourth (unfavorable) quartiles had rapid progression (HR = 1.39 [95% CI, 0.94-2.06], 1.52 [95% CI, 1.04-2.24], and 2.04 [95% CI, 1.41-2.94], respectively). Recent exposure to tenofovir disoproxil fumarate was associated with rapid progression (HR = 1.36 [95% CI, 1.06-1.76]). DISCUSSION: An individual polygenic risk score is associated with rapid progression in Swiss PWH, when analyzed in the context of clinical and antiretroviral risk factors.

Contribution of Genetic Background and Data Collection on Adverse Events of Anti-human Immunodeficiency Virus (HIV) Drugs (D:A:D) Clinical Risk Score to Chronic Kidney Disease in Swiss HIV-infected Persons With Normal Baseline Estimated Glomerular Filtration Rate.

BACKGROUND: In human immunodeficiency virus (HIV), the relative contribution of genetic background, clinical risk factors, and antiretrovirals to chronic kidney disease (CKD) is unknown. METHODS: We applied a case-control design and performed genome-wide genotyping in white Swiss HIV Cohort participants with normal baseline estimated glomerular filtration rate (eGFR >90 mL/minute/1.73 m2). Univariable and multivariable CKD odds ratios (ORs) were calculated based on the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) score, which summarizes clinical CKD risk factors, and a polygenic risk score that summarizes genetic information from 86 613 single-nucleotide polymorphisms. RESULTS: We included 743 cases with confirmed eGFR drop to <60 mL/minute/1.73 m2 (n = 144) or ≥25% eGFR drop to <90 mL/minute/1.73 m2 (n = 599), and 322 controls (eGFR drop <15%). Polygenic risk score and D:A:D score contributed to CKD. In multivariable analysis, CKD ORs were 2.13 (95% confidence interval [CI], 1.55-2.97) in participants in the fourth (most unfavorable) vs first (most favorable) genetic score quartile; 1.94 (95% CI, 1.37-2.65) in the fourth vs first D:A:D score quartile; and 2.98 (95% CI, 2.02-4.66), 1.70 (95% CI, 1.29-2.29), and 1.83 (95% CI, 1.45-2.40), per 5 years of exposure to atazanavir/ritonavir, lopinavir/ritonavir, and tenofovir disoproxil fumarate, respectively. Participants in the first genetic score quartile had no increased CKD risk, even if they were in the fourth D:A:D score quartile. CONCLUSIONS: Genetic score increased CKD risk similar to clinical D:A:D score and potentially nephrotoxic antiretrovirals. Irrespective of D:A:D score, individuals with the most favorable genetic background may be protected against CKD.

[Incidental finding of a high creatinine]. / Zufallsbefund hohes Kreatinin.

Incidental finding of a high creatinine Abstract. In up to 10 % of patient visiting their General Practitioner and having blood tests an elevated creatinine or reduced kidney function are detected incidentally by the often automatically reported estimation of glomerular filtration rate (eGFR) by a creatinine-based formula. The most important step in this situation is to evaluate whether reduced kidney function is due to chronic kidney disease or whether the patient presents with an acute kidney injury (AKI). Early detection of AKI is crucial as any delay in accurate therapy can lead to further decline of kidney function and elevated mortality. In addition, intrinsic kidney diseases, which are less common should not be missed because early access to specialised management is crucial. Clinical history including history of medication, context of consultation, clinical evaluation and additional laboratory values will help to provide a first suspicion diagnosis. Further investigations (abdominal sonography, urinary sediment, proteinuria) will help to confirm the diagnosis. In any case of absence of an obvious cause of AKI, young patient, threatening severe renal insufficiency with rapid progression of kidney failure or suspicious laboratory abnormalities, the patient should be referred without any delay to a nephrologist for further evaluation and management.

Proteinuria Assessment and Therapeutic Implementation in Chronic Kidney Disease Patients-A Clinical Audit on KDIGO ("Kidney Disease: Improving Global Outcomes") Guidelines.

Background/Objectives: Chronic kidney disease (CKD) is a major health problem with a rising prevalence due to comorbidities like diabetes and hypertension. The aim of this research was to audit the assessment and therapeutic management of proteinuria in CKD patients at the Cantonal Hospital Baselland (KSBL) in Switzerland and determine associations between patient comorbidities, rehospitalisation, death, and the quality of therapeutic management. Methods: We analysed data from 427 adults with CKD (eGFR < 45 mL/min/1.73 m2) hospitalised on the internal medicine ward in 2022. Results: The mean age was 85 years (range: 79-89), 45.9% were female, and the median eGFR was 32.8 mL/min/1.73 m2 (range: 25-40). Proteinuria assessment was performed in 120 (28.1%) patients (the ProtU group), and a corresponding treatment was prescribed in 59%. The ProtU group had a higher quota of patients with diabetes (44.1% vs. 33%, p = 0.048) and obesity (21.2% vs. 12.5%, p = 0.039) when compared to the group without proteinuria assessment (the Ustix group). Twelve-month survival was not significantly different between the groups (HR: 0.75; 95% CI: 0.488-1.154; p-value = 0.191). However, survival was significantly better in patients who received an antiproteinuric treatment compared to those who did not (HR: 0.30; 95% CI: 0.121-0.0761; p = 0.011). Conclusions: Improvements need to be made in managing CKD at the KSBL in accordance with the guidelines.

Intermediate-term outcome of single kidney grafts from pediatric donors weighing 10-14 kg in adult recipients.

BACKGROUND: Kidneys from pediatric donors weighing <10 kg are preferably transplanted en bloc, while kidneys from donors weighing >15 kg can be safely transplanted as single kidneys. However, single kidney transplantation from donors weighing 10-14 kg is controversial and has not been well investigated. METHODS: We analyzed the outcome of 15 recipients of single kidneys from donors weighing 10-14 kg (study group) with 40 recipients receiving an allograft from ideal deceased donors (control group). RESULTS: After a follow-up of three yr, death-censored graft survival was 100% in both groups. The calculated creatinine clearance was lower in the study group at six months (53 vs. 71 mL/min; p = 0.01) and similar at 12 months (68 vs. 68 mL/min; p = 0.48), 24 months (81 vs. 70 mL/min; p = 0.58), and 36 months (74 vs. 69 mL/min; p = 0.59). Urinary albumin/creatinine ratios were comparable between the two groups up to two yr. At three yr, urinary albumin/creatinine ratios were higher in the study group than the control group (10.5 vs. 0.9 mg/mmol; p = 0.007). Surveillance biopsies at three and six months post-transplant revealed no evidence for focal segmental glomerulosclerosis in the study group. CONCLUSIONS: Transplantation of single pediatric kidneys from donors weighing 10-14 kg into adult recipients provides excellent intermediate-term outcomes. Low-grade albuminuria, three yr post-transplant, might indicate late-onset hyperfiltration injury.

[Not Available]. / Proteinurie - Bedeutung und diagnostisches Vorgehen.

Proteinuria is a common incidental finding in primary care. A systematic approach is necessary to differentiate benign causes of proteinuria from severe kidney diseases. Glomerular proteinuria is the predominant pathophysiologic mechanism of the three types of proteinuria (i. e. glomerular, tubular and "overflow") and usually corresponds to urinary protein excretion > 1 g per day. When urine dipstick analysis is positive a quantitative measurement of urinary protein excretion is necessary. Therefore, quantification by albumin/creatinine ratio measurement in a random urine specimen is an important and reliable next step. Patients with persistent proteinuria, in whom the underlying aetiology remains unclear, besides extensive analysis or with a proteinuria ≥ 1 g per day should be referred to a nephrologist for further diagnosis and timely therapeutic interventions.

Excellent Clinical Long-Term Outcomes of Kidney Transplantation From Small Pediatric Donors (Age ≤ 5 Years) Despite Early Hyperfiltration Injury.

Background: The use of small pediatric donors (age ≤ 5 years and body weight < 20kg) for adult transplant recipients is still regarded controversially in terms of early complications, long-term outcomes, and development of hyperfiltration injury due to body size mismatch. Objective: To investigate long-term outcomes of adult renal allograft recipients receiving a kidney from small pediatric donor (SPD) in terms of kidney function and early features of hyperfiltration injury such as histological changes and proteinuria. Design: Retrospective, single center study. Settings: Transplant center of the University Hospital of Basel, Switzerland. Patients: Adult renal allograft recipients receiving a kidney from a small pediatric donor at our center between 2005 and 2017. Methods: The outcome of 47 transplants from SPD were compared with 153 kidney transplants from deceased-standard criteria donors (SCD) occurring during the same time period. Incidence of clinical signs of hyperfiltration injury (eg, proteinuria) was investigated. According to our policy, surveillance biopsies were taken at 3 and 6 months post-transplant and were evaluated in terms of signs of hyperfiltration injury. Results: At a median follow-up of 2.3 years post-transplant, death-censored graft survival of SPD was comparable to transplants from SCD (94% vs 93%; P = .54). Furthermore, allograft function at last follow-up (estimated glomerular filtration rate-Modification of Diet in Renal Disease) was significantly higher in pediatric transplant (80 vs 55 ml/min/1.73 m2, P = .002). We found histological signs of early hyperfiltration injury in 55% of SPD. There was an equally low proteinuria in both groups during follow-up. Limitations: It is a single center and retrospective observational study with small sample size. The outcomes were investigated in a well-selected population of recipients with low body mass index, low immunological risk, and well-controlled hypertension and was not compared with equal selected group of recipients. Conclusions: Early histological and clinical signs of hyperfiltration injury in SPD is frequent. Despite the hyperfiltration injury, there is an equal allograft survival and even superior allograft function in SPD compared with SCD during follow-up. This observation supports the concept of high adaptive capacity of pediatric donor kidneys.

Contexte: Le recours à de très jeunes donneurs pédiatriques (âge: ≤ 5 ans; poids < 20 kg), pour des greffes chez des receveurs adultes, suscite encore des préoccupations quant aux complications précoces, aux résultats à long terme et au développement de lésions d'hyperfiltration liées à la disproportion de taille corporelle. Objectif: Examiner les résultats à long terme de patients adultes greffés rénaux ayant reçu l'organe d'un très jeune donneur pédiatrique (TJDP), soit la fonction rénale et les signes précoces de lésions d'hyperfiltration (p. ex. changements histologiques et protéinurie). Type d'étude: Étude rétrospective dans un seul établissement. Cadre: Le centre de transplantation de l'hôpital universitaire de Bâle (Suisse). Sujets: Les adultes ayant reçu une greffe rénale provenant d'un très jeune donneur pédiatrique dans notre centre entre 2005 et 2017. Méthodologie: Les résultats de 47 transplantations impliquant des TJDP ont été comparés à ceux de 153 transplantations rénales survenues au cours de la même période, mais impliquant des donneurs décédés répondant aux critères standard (DDCS). L'incidence des signes cliniques de lésions d'hyperfiltration (p. ex. protéinurie) a été étudiée. Selon notre politique, des biopsies de surveillance ont été réalisées à 3 et 6 mois post-transplantation et évaluées pour les signes d'hyperfiltration. Résultats: Lors d'un suivi médian de 2,3 ans post-transplantation, le pourcentage de survie du greffon (censurée pour les décès) provenant de TJDP était comparable à celui de DDCS (94 % c. 93 %; p = 0,54). De plus, la fonction du greffon lors du dernier suivi (DFGe basé sur l'équation MDRD) était significativement plus élevée dans les cas de transplantation pédiatrique (80 ml/min/1,73 m2 contre 55 ml/min/1,73 m2; p=0,002). Des signes histologiques de lésions précoces dues à une hyperfiltration ont été observés dans 55 % des cas impliquant un TJDP. La protéinurie était peu importante et équivalente dans les deux groupes au cours du suivi. Limites: Il s'agit d'une étude observationnelle et rétrospective menée dans un seul centre et sur un faible échantillon. Les résultats ont été obtenus dans une population bien précise de receveurs avec un IMC peu élevé, un risque immunologique faible et une hypertension bien contrôlée; ces résultats n'ont pas été comparés à un autre groupe de receveurs équivalents. Conclusion: Des signes histologiques et cliniques précoces de lésion d'hyperfiltration sont fréquents chez les TJDP. Malgré cela, pendant la période de suivi, la survie de greffon provenant d'un TJDP s'est avérée comparable à celles d'organes provenant de DDCS et la fonction supérieure. Cette observation appuie l'hypothèse d'une grande capacité d'adaptation des reins provenant de donneurs pédiatriques.

[The risk of living kidney donation]. / Wer kann mit welchem Risiko eine Niere spenden?

Living kidney donation was started in the seventies in Switzerland and since the year 2000 all transplant centers in Switzerland perform this procedure. It shows excellent long-term results in terms of graft and patient survival with an acceptable risk for the donor. Due to the shortage of deceased kidney donors available for transplantation and the rising number of patients on the waiting list, there is an increasing pressure towards living kidney donation reflected by the rise of living-donor kidney transplantation since the last decade. Due to this pressure it is important to do a very careful medical and psychological evaluation. In addition it is important to inform the donors about the possible risks of kidney donation which includes the short as well as the long term prognosis. This is only possible with a prospective long-term analysis of all living donor in specific country. In Switzerland this is guaranteed by the Swiss Organ Living Donor Health Registry (SOL-DHR), which is world wide the only prospective national donor registry with an actual follow up of 18 years. The following manuscript summarizes the medical and psychological evaluations of living kidney donors and delivers insight in the risks and the possible long-term effects of living kidney donation.