Outcomes of Patients With Autosomal Dominant Polycystic Kidney Disease Prescribed SGLT2 Inhibitors in British Columbia: A Single-Arm Retrospective Cohort Study

Background:Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) have revolutionized the management of type 2 diabetes, heart failure, and chronic kidney disease (CKD), all comorbidities which are also highly prevalent among individuals...

Evaluation of urine biomarkers of kidney injury in polycystic kidney disease

Detection of autosomal dominant polycystic kidney disease by NMR spectroscopic fingerprinting of urine

Purpose of ReviewType 2 diabetes mellitus (T2DM) is a prevalent disease with the severe clinical implications including myocardial infarction, stroke, and kidney disease. Therapies focusing on glycemic control in T2DM such as biguanides, sulfonylureas, thiazolidinediones, and insulin-based regimens have largely failed to substantially improve cardiovascular and kidney outcomes. We review the recent findings on sodium-glucose co-transporter type 2 (SGLT2) inhibitors which have shown to have beneficial cardiovascular and kidney-related effects.Recent FindingsSGLT2 inhibitors are a new class of diabetic medications that reduce the absorption of glucose in the kidney, decrease proteinuria, control blood pressure, and are associated with weight loss. SGLT2 inhibitors provide complementary therapy independent of insulin secretion or action with proved glucose-lowering effects. Recent placebo-controlled clinical trials have demonstrated that these medications can decrease cardiovascular death, progression of kidney disease, and all-cause mortality in diabetic and non-diabetic patients. Interestingly, SGT2 inhibitors such as dapagliflozin have also proven to decrease heart failure admissions and cardiovascular endpoints in non-diabetic patients, suggesting pleiotropic effects. The exact mechanisms responsible for reductions in atherosclerotic heart disease, need for kidney replacement therapy, and progressive kidney disease remain unknown. While regulation of glomerular hyperfiltration, albuminuria, and natriuresis may be part of the explanation, it is possible that complex cellular effects including energy balance optimization, downregulation of oxidative stress, and modulation of pro-inflammatory signaling pathways are associated with favorable outcomes observed in large clinical studies.ConclusionSGLT2 inhibitors are novel antidiabetic medications with immense utility in the management of patients with T2DM. Furthermore, SGLT2 inhibitors have demonstrated to reduce the progression to advanced forms of kidney disease and its associated complications. These medications should be front and center in the management of patients with diabetic kidney disease with and without chronic kidney disease as they confer protection against cardiovascular/renal death and improve all-cause mortality. Future studies should evaluate the benefits and implications of early initiation of SGLT2 inhibitors, as well as the long-term effects of this therapy.

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results in animal models.

A novel class of oral glucose lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2is), has shown additional beneficial effects on body weight, serum uric acid levels, blood pressure, and cardiac and renal function. Conflicting data have been published regarding the potential risk of acute kidney injury (AKI) when using SGLT2is. Aim of this manuscript was to review the current literature on this issue. SGLT2isinduce a mild acute decline in estimated glomerular filtration rate, attributed to the effect of proximal tubular natriuresis on tubuloglomerular feedback through increased macula densa sodium delivery, leading to afferent arteriole vasoconstriction and reduced intraglomerular pressure. This functional effect with a subsequent rise in serum creatinine fulfills the creatinine-basedcriteria for AKI,as defined in clinical practice and trial settings. Other proposed potential mechanisms as tohow SGLT2islead to AKI include osmotic diuresis leading to volume depletion, increased urinary uric acid levels, intratubular oxidative stress, local inflammation and tubular injury. Despite the warning published by the US Food and Drug Administration in 2016 about a potential risk of AKI and the report of some clinical cases of AKI after treatment with SGLT2is, large observational real-life retrospective studies, randomized controlled trials and propensity-matched analyses of data from clinical practice unambiguously demonstrate that SGLT2is are safe for the kidney and do not predispose to AKI. In conclusion, while we can probably stop worrying about AKI risk when using SGLT2is, the question whether these agents should be withheld in the presence of clinical situations at high risk for AKIremains unaddressed.

Background:Sodium-Glucose Cotransporter Type 2 Inhibitors (SGLT2i) are a revolutionary second-line treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits.Objectives:To emulate the idealized target trials examining head-to-head...

Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) have a complex relationship with the kidney so that their use in patients with type 2 diabetes (T2DM) and diabetic kidney disease (DKD) has long been challenged. Areas covered: SGLT2is in patients with DKD are discussed: renal mechanisms of action, PK/PD characteristics, clinical use in patients with stage 3 DKD, effects on estimated glomerular filtration rate (eGFR) and albuminuria, cardiovascular, and renal outcomes according to renal function, overall and renal safety, SGLT2is new place in updated guidelines. Expert opinion: Whereas initial concerns (reduced glucose-lowering efficacy, early reduction in eGFR) led to restrictions in the use of SGLT2is in patients with DKD, recent positive observations have completely reversed the scene. Indeed, albuminuria is reduced and eGFR is preserved in the long term by SGLT2is. A significant reduction in cardiovascular events and hard renal outcomes was reported even in patients with eGFR 30–60 mL/min/1.73 m2. The overall safety profile of SGLT2is is not altered in patients with mild to moderate DKD, with a reduced (rather than increased) risk of acute renal injury. This positive benefit/risk balance led recent guidelines to recommend SGLT2is in patients with T2DM and mild to moderate DKD, especially if albuminuria.

Chronic kidney disease is a prevalent complication of type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) have a unique mode of action targeting the kidney. As their glucose-lowering potency declines with the reduction in estimated glomerular filtration rate, their clinical use in patients with T2DM with chronic kidney disease has been submitted to restriction. However, recent observations demonstrated that SGLT2is reduce the progression of renal impairment in patients with mild-to-moderate chronic kidney disease, with or without albuminuria. Furthermore, SGLT2is reduce the incidence of cardiovascular events in patients with T2DM at high cardiovascular risk, independently of baseline estimated glomerular filtration rate. Thus, recent guidelines recommend the prescription of SGLT2is in patients with T2DM with mild-to-moderate chronic kidney disease defined by an estimated glomerular filtration rate between ≥ 30 and < 90mL/min/1.73m2 and/or albuminuria. The present comprehensive review describes the pharmacokinetic/pharmacodynamic properties of SGLT2is commercialised worldwide and in Japan in patients with T2DM with mild, moderate and severe chronic kidney disease. Drug exposure increases when the estimated glomerular filtration rate declines but without a clear-cut relationship with the severity of chronic kidney disease and in a rather moderate amplitude that most often does not require a dose reduction in the presence of mild-to-moderate chronic kidney disease. The urinary glucose excretion steadily declines with the reduction in estimated glomerular filtration rate. This may explain a lower effect on glucose control, yet the positive effects on body weight and blood pressure still remain. The efficacy and safety of these SGLT2is are analysed among patients with stages 3a and 3b chronic kidney disease in placebo-controlled randomised clinical trials, with almost similar results in Asian and non-Asian individuals with T2DM. In summary, there is no reason not to prescribe SGLT2is in patients with T2DM with mild-to-moderate chronic kidney disease, especially if the aim is to benefit from cardiovascular and/or renal protection.

ECE1 gene variant shows tendency toward chronic kidney disease advancement among autosomal polycystic kidney disease patients

Michael R. Charlton, William J. Wall, Akinlolu O. Ojo, Pere Gines, Stephen Textor, Fuad S. Shihab, Paul Marotta, Marcelo Cantarovich, James D. Eason, Russell H. Wiesner, Michael A. Ramsay, Juan C. Garcia-Valdecasas, James M. Neuberger, Sandy Feng, Connie L. Davis, Thomas A. Gonwa, and the International Liver Transplantation Society Expert Panel Mayo Clinic, Rochester MN; Department of General Surgery, London Health Science Center, London, Ontario, Canada; Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; Liver Unit, Hospital Clinic, University of Barcelona School of Medicine, Barcelona, Spain; Department of Nephrology, University of Utah School of Medicine, Salt Lake City, UT; Medical School, University of Western Ontario, London, Ontario, Canada; Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada; Transplant Institute, University of Tennessee, Memphis, TN; Baylor University Medical Center, Dallas, TX; Hospital Clinic I Provincial, Barcelona, Spain; Queen Elizabeth Hospital, Birmingham, England; Department of Transplant Surgery, University of California San Francisco Medical Center, San Francisco, CA; Department of Medicine, University of Washington Medical Center, Seattle, WA; and Mayo Clinic, Jacksonville, FL

Introduction Sodium-glucose co-transporter type 2 inhibitors (SGLT2is) were developed as glucose-lowering agents for the management of type 2 diabetes (T2D). Unexpectedly, they showed a significant reduction in hospitalization for heart failure and hard renal outcomes in patients with and without T2D. Underlying mechanisms remain a matter of debate. Areas covered We summarize the protective renal effects of SGLT2is in patients with cardiovascular disease, chronic kidney disease (CKD, especially with albuminuria) or heart failure; a description of the safety of SGLT2is, with a special focus on the risk/benefit balance in people with stage 3 CKD; a comprehensive discussion of mechanisms that could explain nephro-protection; a reappraisal of the positioning of SGLT2is in recent international guidelines. Expert opinion Several mechanisms could contribute to improved renal prognosis with SGLT2is, among which a reduction in intraglomerular pressure by restoring the tubuloglomerular feedback, a diuretic effect that contributes to lower albuminuria and renal decongestion, especially if fluid overload is present, a reduction in renal oxygen consumption, an improvement of heart failure status with less cardiorenal syndrome and a lower risk of acute renal injury. All these effects may be mutually not exclusive, and their respective contribution may differ according to patient characteristics.

Patients with type 2 diabetes mellitus (T2DM) are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD), which are important causes of disabling and death in patients with T2DM. For the prevention and management of ASCVD or CKD, cardiovascular risk factors should be systematically evaluated, and ASCVD and CKD should be screened in patients with T2DM. In this consensus, we recommended that metformin should be used as the first-line therapy for patients with T2DM and ASCVD or very high cardiovascular risk, heart failure (HF) or CKD, and should be retained in the treatment regimen unless contraindicated or not tolerated. In patients with T2DM and established ASCVD or very high cardiovascular risk, addition of a glucagon-like peptide 1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter type 2 (SGLT2) inhibitor with proven cardiovascular benefits should be considered independent of individualised glycated haemoglobin (HbA1C ) targets. In patients with T2DM and HF, an SGLT2 inhibitor should be preferably added regardless of HbA1C levels. In patients with T2DM and CKD, SGLT2 inhibitors should be preferred for the combination therapy independent of individualised HbA1C targets, and GLP-1RAs with proven renal benefits would be alternative if SGLT2 inhibitors are contraindicated. Moreover, the prevention of hypoglycaemia and management of multiple risk factors by comprehensive regimen, including lifestyle intervention, antihypertensive therapies, lipid-lowering treatment and antiplatelet therapies, should be kept in mind in treating patients with T2DM and ASCVD, HF or CKD.

A term, large-for-gestational age boy is transferred from an outside hospital with a right anterior chest wall mass noted since birth. His mother is a healthy 33-year-old gravida 4, para 4 woman with good prenatal care and normal prenatal laboratory values who had an uncomplicated pregnancy and elective cesarean delivery. None of the patient’s siblings or family members have had similar masses.On physical examination the patient is well-appearing and moving all 4 extremities spontaneously without obvious limitations. Vital signs on admission to the hospital are normal. There is a nontender, boggy, fluctuant, flesh-colored, grapelike mass from his right nipple to the midaxillary line that extends to the right upper arm, with dimpling of the skin throughout the right upper extremity (Fig 1). No bruit is heard over the lesion. There is no palpable bony abnormality. Radial pulses are 2+. Capillary refill is less than 2 seconds. His lungs are clear to auscultation. The cardiovascular examination reveals a normal heart rate, rhythm, S1, and S2 and no murmurs. The abdomen is soft, nontender, and nondistended, with no palpable masses or hepatosplenomegaly.Chest radiography is normal. Complete blood cell count with differential count is normal. Ultrasonography of the right superolateral chest shows a multiloculated fluid collection with undulating borders measuring 6 × 1.7 cm. Magnetic resonance imaging (MRI) with contrast of the chest and right upper extremity reveals a multiloculated macrocystic mass in the superficial right chest wall, additional cysts in the right arm, and a partially cystic right mediastinal mass (Figs 2 and 3). MRI also shows multiple cysts in both kidneys (Fig 4). Review of the findings from MRI and genetic testing reveal the diagnoses.The differential diagnosis includes lymphatic malformation, venous malformation, vascular tumor, arteriovenous malformation, arteriovenous fistula, and capillary malformation. The patient was diagnosed as having lymphatic malformation. In addition, rapid genome sequencing revealed de novo pathogenic variant of PKD1 mutation, supporting an incidental second diagnosis of autosomal dominant polycystic kidney disease (ADPKD).Lymphatic malformations are a type of vascular anomaly. The International Society for the Study of Vascular Anomalies stratifies vascular anomalies into vascular tumors (benign, locally aggressive or borderline, and malignant) and vascular malformations (simple, combined, anomalies of major named vessels, and vascular malformations associated with other anomalies). (1)(2) Lymphatic malformations are low-flow, nonmalignant vascular malformations of the lymphatic system with dilated lymphatic channels or cysts thought to occur during lymphatic development.Lymphatic malformations can affect 1 location or can be loculated and/or multifocal (eg, lymphangiomatosis). (3) Lymphatic malformation is an umbrella term that includes all subtypes of lymphatic malformations, including cystic lymphatic malformations (macrocystic, microcystic, or mixed), generalized lymphatic anomalies such as kaposiform lymphangiomatosis, channel-type lymphatic malformation, acquired progressive lymphatic anomaly (acquired progressive lymphangioma), and primary lymphedema. Lymphatic malformations can affect any area of the body but most commonly occur in the head and neck regions, followed by the extremities. (4) They are classified as macrocystic, microcystic, or mixed. Most are noted at birth or within the first 2 years after birth.Superficial lymphatic malformations or deep vascular lesions may have no skin discoloration. In contrast, superficial arterial, capillary, or venous vascular anomalies can appear red, pink, violaceous, or blue, depending on the mix of oxygenated (arterial) or deoxygenated (venous) blood. Superficial lymphatic malformations can have clear vesicles or pitting of the skin or appear bruised if bleeding occurs within the malformation. Venous malformations are often bluish, soft, and compressible papules. Capillary malformations are often pink, red, or purple flat macules or patches. High-flow malformations, such as arteriovenous malformations and arteriovenous fistulas, can have a palpable bruit or thrill. Vascular anomalies can cause overgrowth and swelling in the affected area, which could cause pain.Lymphatic malformations can be associated with other anomalies. Gorham-Stout syndrome, also known as vanishing bone disease, is a rare condition characterized by proliferation of lymphatic vessels adjacent to single or multiple bones, leading to osteolysis and resorption of bone, oftentimes the ribs, spine, pelvis, skull, clavicle, or jaw. (5) Several PIK3CA-related overgrowth spectrum conditions also have lymphatic malformations, such as Klippel-Trenaunay syndrome, a rare congenital syndrome characterized by cutaneous capillary malformations (port-wine stain), vascular or lymphatic malformations, and limb overgrowth. (1)(6) Many patients with lymphatic malformations have an activating somatic PIK3CA gene mutation. (7) This was not the case for our patient.Diagnosis of vascular malformation or neoplasm is often made clinically and confirmed by imaging. For initial imaging, the 2019 American College of Radiology Appropriateness Criteria for Clinically Suspected Vascular Malformation of the Extremities deems magnetic resonance angiography with and without contrast, MRI with and without contrast, computed tomographic (CT) angiography with contrast, and duplex Doppler ultrasonography as appropriate for suspected vascular malformation of the extremity presenting with physical deformity. (8) However, because our patient also had a suspected abnormality in the chest wall, MRI or magnetic resonance angiography with and without contrast would be the best initial study to better evaluate deeper lesions than ultrasonography and better evaluate soft tissue contrast than CT angiography.The presence of renal cysts initially raised concern for underlying lymphangiomatosis. Lymphangiomatosis is the term used to describe lymphatic malformations in multiple organs. (3) It can affect any region of the body, although it is most common in the neck, axilla, retroperitoneum, and mediastinum. Renal lymphangiomatosis in pediatric patients is rare but should be included in the differential diagnosis for conditions such as ADPKD, nephroblastomatosis, lymphoma, and hydronephrosis with perinephric urinoma. (9) Several case reports describe initial misdiagnosis of renal lymphangiomatosis as ADPKD. Imaging and genetic testing can help differentiate between renal lymphangiomatosis and ADPKD. In renal lymphangiomatosis, renal cysts are central in the renal sinus, whereas in ADPKD, renal cysts are peripheral and parenchymal, as was seen with this patient. (9) In addition, the patient’s rapid genome sequencing reveals de novo pathogenic variant of PKD1 mutation, which supports a diagnosis of ADPKD being a separate etiology for renal cysts from that underlying the lymphatic malformations in the chest and right upper extremity. Differentiation between renal lymphangiomatosis and ADPKD can affect the treatment regimen and prognosis. A case report describing an infant with biopsy-proven bilateral renal lymphangiomatosis with 1-year follow-up suggests a self-limiting course in some patients, although it can expand before regression. (10) Successful treatment for renal lymphangiomatosis with sclerotherapy has been described. (3)(9)A case report describing an adult with comorbid lymphangiomatosis and ADPKD hypothesized a link between ADPKD and lymphangiomas as cystic pathologies sharing common genetic and congenital processes; however, no genetic mechanism has been identified. (11)ADPKD is the most common hereditary kidney disease, with a prevalence of 1:1,000 to 1:2,500. Patients with ADPKD develop cysts in the kidney parenchyma, which often leads to end-stage kidney disease by age 50 to 60 years. Our patient’s incidental diagnosis of ADPKD is atypical for several reasons. There was no family history, he developed cysts in the neonatal period, and his presenting complaint was lymphatic malformations. Our patient had a de novo PKD1 mutation, the most common mutation seen in ADPKD. Patients with PKD1 mutations have a less favorable kidney prognosis than patients with PKD2 mutations, who have end-stage kidney disease in their 70s and 80s. The Predicting Renal Outcomes in Polycystic Kidney Disease score combines predictive genetic factors with clinical information to predict risk of progression to end-stage kidney disease for patients with ADPKD in patients older than 35 years. (12) ADPKD is typically diagnosed using renal ultrasonography in patients with an affected first-degree relative. Genetic analysis can be useful in very young patients without a family history of ADPKD, as in our patient, who was found to have a de novo PKD1 mutation.Symptoms from lymphatic malformations vary depending on location of involvement and extent of invasion. Management varies depending on location, size and symptoms (including compression or obstruction of adjacent structures), infection, and interference with quality of life, including cosmetic concerns. Generally, microcystic lymphatic malformations are more challenging to treat than are macrocystic lymphatic malformations because they are less accessible for aspiration or sclerosing. (1)Observation for potential spontaneous regression can be appropriate for small lymphatic malformations without compromise of other systems. (13) Compression dressing is a conservative, first-line option for symptomatic treatment of lymphatic malformations limited to the extremities to prevent pain or growth of the malformation. (4) Treatment options for large or symptomatic lymphatic malformations include sclerotherapy, endovenous laser ablation, radiofrequency ablation, and surgical resection. Drug therapy with sirolimus, sildenafil, or propranolol has been described in case reports. Antibiotics should be used to treat infected lymphatic malformations.Clinical trials in adults with ADPKD show that angiotensin-converting enzyme inhibitors and possibly vasopressin antagonists decrease renal cyst growth. (14) A randomized controlled trial with tolvaptan, a selective vasopressin antagonist, for pediatric ADPKD is underway for children aged 12 to 17 years; results are not yet available. (15) Schaefer et al suggest angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for management of hypertension and proteinuria in the setting of pediatric ADPKD. (15) In addition, there is limited evidence that statin therapy slows the progression of structural kidney disease in children and young adults with ADPKD. (16)The patient was evaluated by a multidisciplinary team including surgery, hematology/oncology, nephrology, genetics, and interventional radiology; he was referred for sclerotherapy but was lost to follow-up.Five months later he presented with cough and was diagnosed as having a parainfluenza infection. Chest radiography revealed airway compromise; CT showed that the intrathoracic extent had dramatically increased, resulting in mediastinal shift and tracheal narrowing (Fig 5). Dark, sanguineous fluid was drained from the lesion, and sclerotherapy was performed using bleomycin. The postsclerotherapy radiograph showed mass reduction and improved lung expansion.Persistent hypertension was treated with enalapril. Repeated renal ultrasonography, compared with postnatal imaging, showed an enlarging right cyst and a new left cyst. Intrathoracic sclerotherapy was repeated 40 days later. Further treatment will be required.

Autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney disease are caused by mutations in Pkd1/Pkd2 and Pkhd1, which encode polycystins (PCs) and fibrocystin/polyductin (FPC). Our recent study reported that a deficiency in FPC increases the severity of cystic disease in Pkd2 mutants and down-regulates PC2 in vivo, but the precise molecular mechanism of these effects is unknown (Kim, I., Fu, Y., Hui, K., Moeckel, G., Mai, W., Li, C., Liang, D., Zhao, P., Ma, J., Chen, X.-Z., George, A. L., Jr., Coffey, R. J., Feng, Z. P., and Wu, G. (2008) J. Am. Soc. Nephrol. 19, 455-468). In this study, through the use of deletion and mutagenesis strategies, we identified a PC2-binding domain in the intracellular C terminus of FPC and an FPC-binding domain in the intracellular N terminus of PC2. These binding domains provide a molecular basis for the physical interaction between PC2 and FPC. In addition, we also found that physical interaction between the binding domains of PC2 and FPC is able to prevent down-regulation of PC2 induced by loss of FPC. In vivo, we generated a mouse model of ADPKD with hypomorphic Pkd2 alleles (Pkd2nf3/nf3) and show that PC2 down-regulation is accompanied by a phenotype similar to that of Pkhd1(-/-) mice. These findings demonstrate a common mechanism underlying cystogenesis in ADPKD and ARPKD and provide insight into the molecular relationship between PC2 and FPC.