The unresolved epidemic of chronic kidney disease of uncertain origin (CKDu) around the world: A review and new insights.

EPIDEMIOLOGY: An increasing number of inhabitants of Central America have developed a form of chronic kidney disease of unknown cause, named Mesoamerican nephropathy (MeN). Because similar epidemics have been reported in other parts of the world, such as Sri Lanka, India, Egypt, and Tunisia, this condition is currently called chronic kidney disease of uncertain origin (CKDu). CLINICAL PRESENTATION: This disease is characterized by minimal proteinuria, leukocyturia, hyperuricemia, hypokalemia reduced glomerular filtration rate, and renal tubular dysfunctions. Pathology: The kidneys manifest tubulo-interstitial nephritis and glomerulosclerosis. Electron microscopy shows large dimorphic lysosomes with dark electron-dense aggregates. Potential causes: The cause(s) of this disease remain largely unknown. Several hypotheses have been proposed including infections, dehydration, global warming, hyperuricemia, exposure to agro-chemicals or heavy metals, and genetic susceptibility. This review addresses a mounting body of evidence suggesting that the disease may be the result of exposure to a variety of water contaminants combined with volume depletion. THERAPY: Absent a clear understanding of the causes of the disease, no specific therapeutic interventions can be recommended. Preliminary studies suggest that reduction of working hours, frequent rest in shaded area, and administration of purified water may reduce the risk of CKDu.

Renovascular disease: Is there still a role for revascularization?
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There are substantial doubts pertaining to the clinical usefulness of radiological and surgical interventions in the management of renovascular disease, particularly in patients with diffuse atherosclerotic vascular disease. This article reviews the current knowledge on advantages and limitations of interventional techniques in the management of patients with atherosclerotic renovascular disease.
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Acute Declines in Renal Function during Intensive BP Lowering: Implications for Future ESRD Risk.

The magnitude of decline in renal function that should be tolerated during intensive BP lowering and its association with risk of ESRD are unclear. To determine whether the acute declines in kidney function in the intensive BP lowering arm of two trials in CKD associated with higher risk of ESRD, we performed a retrospective study of 899 African American Study of Kidney Disease and Hypertension (AASK) and 761 Modification of Diet in Renal Disease (MDRD) Trial participants previously randomized to strict versus usual BP control. The predictor was the percentage decline in eGFR (<5%, 5% to <20%, or ≥20%) between randomization and months 3 and 4 of the trial (time to achieve BP goals). ESRD was the outcome of interest. Compared with a <5% eGFR decline in the usual BP arm, a 5% to <20% eGFR decline during intensive BP lowering did not associate with a higher risk of ESRD in the AASK (adjusted hazard ratio [aHR], 1.19; 95% confidence interval [95% CI], 0.84 to 1.68) or the MDRD Trial (aHR, 1.08; 95% CI, 0.84 to 1.40). However, a 5% to <20% eGFR decline in the usual BP arm associated with higher risk of ESRD in AASK (aHR, 1.83; 95% CI, 1.30 to 2.57) and MDRD Trial (aHR, 1.62; 95% CI, 1.25 to 2.11). A ≥20% eGFR decline associated with higher risk of ESRD in both strict and usual BP arms. Thus, acute eGFR declines ≥20% during intensive BP lowering identified a subset of patients at higher risk for adverse outcomes.

Con: Mesoamerican nephropathy: is the problem dehydration or rehydration?

In recent years, an increasing number of inhabitants of Central America have developed a form of chronic kidney disease, now named Mesoamerican nephropathy. This disease is characterized by minimal proteinuria, hyperuricemia, hypokalemia and reduced glomerular filtration rate. Histologically the kidneys manifest tubulointerstitial nephritis. The cause(s) of this disease remain unknown. Some have proposed that dehydration, in combination with hyperuricemia, may be primarily responsible for Mesoamerican nephropathy. In this article, I propose the hypothesis that the disease may be largely due to rehydration with large amounts of contaminated water, whereas dehydration would play only a contributing role.

Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial.

BACKGROUND AND PURPOSE: Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins' pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100-190 mg/dL). METHODS: We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m2; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m2; n=1600) chronic kidney disease overall and by glycemic status at baseline. RESULTS: Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P=0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m2 in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m2 in those randomized to placebo (P<0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12±0.92 mL/min per 1.73 m2 in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m2 in placebo group during a period of 60 months (P=0.016). CONCLUSIONS: This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00147602.

Dyslipidemia and progression of kidney disease: role of lipid-lowering drugs.

HMG-CoA reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity in patients with normal and abnormal kidney function but not in patients with end-stage kidney disease. Evidence supports a role for statins in delaying the progression of kidney disease in a variety of experimental models in animals. However, the evidence that statins may retard CKD progression in humans is scant. In this review, we critically consider the available data supporting a role for statins in CKD progression in humans and the possibility that there might be differences among statins in regards to effects on the kidneys. Finally, we review the evidence that statins may increase the risk of acute kidney injury.

Is lipid management effective for all stages of CKD?.

Patients with chronic kidney disease (CKD) suffer from high rates of cardiovascular morbidity and mortality. The general approach to traditional cardiovascular risk factor modification via dyslipidemia control has not been thoroughly tested in patients with all stages of CKD. In this article, we review the evidence for statin therapy in patients at various stages of CKD, including patients with CKD on dialysis and patients with kidney transplants.

IgA nephropathy in a patient with ulcerative colitis, Graves' disease and positive myeloperoxidase ANCA.

We report a case of a 38-year old woman with a history of ulcerative colitis and Graves' disease who presented with pyoderma gangrenosum, microscopic hematuria, proteinuria, and positive myeloperoxidase ANCA. A renal biopsy revealed a focal proliferative glomerulonephritis with IgA deposits. All these manifestations are likely secondary to ulcerative colitis or to a common pathogenetic mechanism.

The time to offer treatments for COVID-19.

Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.

The Importance of Understanding the Stages of COVID-19 in Treatment and Trials.

COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan, China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease and the importance of timing for investigation and use of various agents. We considered articles related to COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the medRxiv preprint server. We identified relevant stages of COVID-19 including three periods: pre-exposure, incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or currently in use is likely to provide benefit rather than harm.

Intensive versus conventional therapy to slow the progression of idiopathic glomerular diseases.

BACKGROUND: Chronic kidney disease (CKD) caused by idiopathic glomerular diseases usually is progressive. Inhibition of the renin-angiotensin system (RAS) retards, but does not abrogate, CKD progression. Statins and spironolactone may decrease the rate of CKD progression independently or in addition to RAS inhibition. STUDY DESIGN: Randomized open-label study. SETTING & PARTICIPANTS: We recruited 128 patients (82 men and 46 women) with a clinical diagnosis of idiopathic chronic glomerulonephritis and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) (range, 36-102 mL/min/1.73 m(2)), and urine protein-creatinine ratio ranging from 1.1-5.2 g/g. INTERVENTION: Intensive therapy (a combination of RAS inhibitors [angiotensin-converting enzyme [ACE] inhibitors plus angiotensin receptor blockers [ARBs] plus a high-dose statin and spironolactone) versus conventional therapy (a regimen based on ACE inhibitors with a low-dose statin). OUTCOMES: Changes in eGFR, proteinuria, and adverse events after 3 years of therapy. RESULTS: With intensive therapy, urine protein-creatinine ratio decreased from 2.65 (range, 1.1-5.2) to 0.45 (0.14-1.51) g/g (P < 0.001) and eGFR did not significantly change over time (64.6 +/- 2.1 vs 62.9 +/- 2.9 mL/min/1.73 m(2)). With conventional therapy, urine protein-creatinine ratio decreased from 2.60 (range, 1.32-5.4) to 1.23 (0.36-3.42) g/g (P < 0.001) and eGFR decreased from 62.5 +/- 1.7 to 55.8 +/- 1.9 mL/min/1.73 m(2) (P < 0.001). Comparison of the decreases in proteinuria and GFR between intensive versus conventional therapy was significantly different starting in the 1st and 12th months, respectively. Systolic blood pressure was lower with intensive than conventional therapy (113.5 +/- 1.4 vs 122.7 +/- 1.2 mm Hg; P < 0.01). We found an inverse relationship between percentage of decrease in proteinuria and change in eGFR (P < 0.001). Patients on intensive therapy were more likely to develop adverse events, such as hyperkalemia (9 vs 3 patients in the conventional therapy group) and discontinue therapy (15 vs 8 patients in the conventional therapy group). LIMITATIONS: Open-label design. CONCLUSIONS: A more intensive therapy that includes a combination of ACE inhibitors and ARBs plus high-dose statins and spironolactone may retard CKD progression more effectively than conventional therapy based on ACE inhibitors plus low-dose statin, but may lead to more adverse effects and discontinuation of therapy.

Aldosterone in the pathogenesis of chronic kidney disease and proteinuria.

There has been much recent interest in the role of aldosterone as an independent contributor to the progression of chronic kidney disease. Despite treatment with agents such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, many studies have shown that there is incomplete blockade of the renin-angiotensin cascade evidenced by persistent or rising plasma aldosterone levels despite therapeutic renin-angiotensin blockade. This phenomenon is commonly referred to as "aldosterone escape" and is thought to be one of the main contributors to chronic kidney disease progression despite conventional therapeutics. Animal models of the effects of exposure to exogenous aldosterone demonstrate the development of inflammation and fibrosis in both the myocardium and renal parenchyma. In limited human studies, aldosterone receptor antagonism is associated with decreased proteinuria and improved glomerular filtration rate. Although data support the addition of an aldosterone antagonist to conventional therapy when treating patients with chronic kidney disease, more studies are needed to determine the precise clinical indications and the appropriate safety monitoring.

Hypertension in High School Students: Genetic and Environmental Factors: The HYGEF Study.

Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1(alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele (P=0.011 and P=0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na+ excretion (P=0.0083). Urinary protein tests showed a greater excretion of IL1ß (interleukin 1ß) and interleukin 10 (P<0.0001) in carriers of the ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na+ excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.

Regional expression of NAD(P)H oxidase and superoxide dismutase in the brain of rats with neurogenic hypertension.

BACKGROUND: Single injection of small quantities of phenol into the kidney cortex causes hypertension which is mediated by renal afferent sympathetic pathway activation. This phenomenon can be prevented by superoxide dismutase (SOD) infusion in the lateral ventricle, suggesting the role of superoxide (O(2)(-).) in noradrenergic control of arterial pressure. Since NAD(P)H oxidase is a major source of O(2)(-)., we tested the hypothesis that hypertension in this model may be associated with upregulation of NAD(P)H oxidase in relevant regions of brain. METHODS: NAD(P)H oxidase subunits, mitochondrial (MnSOD) and cytoplasmic (CuZnSOD) SOD were measured in rats 4 weeks after injection of phenol or saline in the left kidney cortex. RESULTS: Phenol-injected rats exhibited hypertension, upregulation of gp91(phox), p22(phox), p47(phox) and p67(phox) in the medulla, gp91(phox) and p22(phox) in pons and gp91(phox) in hypothalamus. This was associated with upregulation of MnSOD with little change in CuZnSOD. CONCLUSIONS: Chronic hypertension in phenol-injected rats is associated with upregulation of NAD(P)H oxidase and hence increased O(2)(-). production capacity in the key regions of the brain involved in regulation of blood pressure. Since reactive oxygen species can intensify central noradrenergic activity, the observed maladaptive changes may contribute to the genesis and maintenance of the associated hypertension.

Role of aldosterone in the progression of chronic kidney disease and potential use of aldosterone blockade in children.

Much focus has been placed on the role of the renin-angiotensin system as a mediator of the progression of chronic kidney disease. Novel therapeutic strategies to inhibit the negative impact of renin-angiotensin activation, including dual therapy with an angiotensin-converting enzyme inhibitor and an angiotensin-receptor blocker, have been suggested to achieve more complete disruption of the renin-angiotensin system. The role played by aldosterone, a target of angiotensin II, in the progression of chronic kidney disease has become a subject of significant interest over the past decade. Experimental studies in animals have shown that persistently elevated aldosterone levels lead to pathohistological changes in the kidney, along with renal and cardiac fibrosis. Incomplete suppression of aldosterone may, therefore, contribute to the deleterious effects of the renin-angiotensin system in the setting of chronic kidney disease. Clinical trials in adults have shown a potential role for mineralocorticoid receptor blockers to delay further the development of end-stage renal disease by completing renin-angiotensin blockade. In adults, mineralocorticoid receptor blockade produces a significant anti-proteinuric effect and has minimal risk of causing hyperkalemia if the condition of the patients is closely monitored. Further studies will need to be conducted to determine whether mineralocorticoid receptor blockers are equally effective and safe for the treatment of chronic kidney disease in children.

Differential distribution of muscle and skin sympathetic nerve activity in patients with end-stage renal disease.

End-stage renal disease (ESRD) is characterized by resting sympathetic overactivity. Baseline muscle sympathetic nerve activity (MSNA), which is governed by baroreflexes and chemoreflexes, is elevated in ESRD. Whether resting skin sympathetic nerve activity (SSNA), which is independent from baroreflex and chemoreflex control, is also elevated has never been reported in renal failure. The purpose of this study was to determine whether sympathetic overactivity of ESRD is generalized to include the skin distribution. We measured sympathetic nerve activity to both muscle and skin using microneurography in eight ESRD patients and eight controls. MSNA was significantly (P = 0.025) greater in ESRD (37.3 +/- 3.6 bursts/min) when compared with controls (23.1 +/- 4.4 bursts/min). However, SSNA was not elevated in ESRD (ESRD vs. controls, 17.6 +/- 2.2 vs. 16.1 +/- 1.7 bustst/min, P = 0.61). Similar results were obtained when MSNA was quantified as bursts per 100 heartbeats. We report the novel finding that although sympathetic activity directed to muscle is significantly elevated, activity directed to skin is not elevated in ESRD. The differential distribution of sympathetic outflow to the muscle vs. skin in ESRD is similar to the pattern seen in other disease states characterized by sympathetic overactivity such as heart failure and obesity.