David B. Simon

Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartters syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelmans syndrome represents the predominant subset of Bartters patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelmans syndrome to the locus encoding the renal thiazide-sensitive Na–Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelmans syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III

Analysis of patients with inherited hypokalaemic alkalosis resulting from salt–wasting has proved fertile ground for identification of essential elements of renal salt homeostasis and blood–pressure regulation. We now demonstrate linkage of this phenotype to a segment of chromosome 1 containing the gene encoding a renal chloride channel, CLCNKB. Examination of this gene reveals loss–of–function mutations that impair renal chloride reabsorption in the thick ascending limb of Henles loop. Mutations in seventeen kindreds have been identified, and they include large deletions and nonsense and missense mutations. Some of the deletions are shown to have arisen by unequal crossing over between CLCNKB and the nearby related gene, CLCNKA. Patients who harbour CLCNKB mutations are characterized by hypokalaemic alkalosis with salt–wasting, low blood pressure, normal magnesium and hyper– or normocalciuria; they define a distinct subset of patients with Bartters syndrome in whom nephrocalcinosis is absent. These findings demonstrate the critical role of CLCNKB in renal salt reabsorption and blood–pressure homeostasis, and demonstrate the potential role of specific CLCNKB antagonists as diuretic antihypertensive agents.

Rare independent mutations in renal salt handling genes contribute to blood pressure variation.

The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes—SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)—causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.

Mutations in the Na-Cl Cotransporter Reduce Blood Pressure in Humans

The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman’s syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called “normal” blood pressure. We hypothesized that the mild salt wasting of Gitelman’s syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman’s syndrome. Through genetic testing, family members were identified as inheriting 0 (n=60), 1 (n=113), or 2 (n=26) mutations in NCCT, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age- and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na+ than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.

Ace inhibitors do not induce recombinant human erythropoietin resistance in hemodialysis patients

Angiotensin-converting enzyme (ACE) inhibitors may exacerbate anemia in patients with chronic renal failure, as well as in dialysis patients. To better answer this question, a prospective, crossover study was conducted to evaluate the effect of ACE inhibitors on recombinant human erythropoietin (rHuEPO) requirements in hemodialysis patients. Patients administered an ACE inhibitor when entering the study remained on this drug for the initial 4 months and were then switched to another antihypertensive agent for 4 more months. Patients not initially administered an ACE inhibitor were switched to lisinopril at 4 months. rHuEPO doses were adjusted using a sliding scale based on weekly laboratory hematocrit values. The inclusion criteria were met by 51 patients undergoing dialysis. Demographics were as follows: 61% were women, 64% were black, 46% had diabetes, average age was 53.2 +/- 13.3 years, and time on hemodialysis was 38.0 +/- 44.5 months. Thirty-three patients completed the study. Hematocrit averaged 32.7% +/- 1.9% while on ACE inhibitor therapy and 33.1% +/- 2.1% off ACE inhibitor therapy (P = 0.217). There was no difference in rHuEPO dose per treatment during each period (3,500 +/- 1,549 U on ACE inhibitor therapy versus 3,312 +/- 1,492 U off ACE inhibitor therapy; P = 0.300). No significant differences were found in degree of blood pressure control or various clinical and laboratory parameters that might be associated with rHuEPO resistance between the two periods. Similarly, no differences were found in hospitalization days, duration of infections, or transfusion requirements. These findings suggest that ACE inhibitors do not contribute to rHuEPO resistance in hemodialysis patients.

A One-Year Trial of In-Center Daily Hemodialysis with an Emphasis on Quality of Life

Background/Aims: Hemodialysis is associated with acute changes in several physiologic factors. Previous studies have suggested significant clinical and quality of life (QOL) benefits of daily hemodialysis (DHD) compared with 3 times weekly hemodialysis (CHD). We conducted a prospective trial to evaluate the effects of switching chronic hemodialysis patients to in-center DHD for a 12-month period. Methods: There were no exclusion criteria. Patients received hemodialysis 6 times per week. The study set a standardized weekly Kt/V (stdKt/V) goal of 3.0. A broad array of clinical parameters was determined. QOL was assessed with multiple instruments. Results: Eleven subjects completed 12 months and 12 completed 6 months on DHD. Significant changes relative to baseline at 12 months of DHD included decreased BP and improvements in QOL parameters by multiple techniques. 100% of patients at 12 months wished to continue DHD. Conclusions: DHD offers advantages over CHD with respect to improved QOL and BP control.

MUTATIONS IN NA(K)CL TRANSPORTERS IN GITELMAN'S AND BARTTER'S SYNDROMES

The successful merging of modern molecular genetics with basic renal physiology is exemplified by the recent description of the molecular basis of two classic diseases of clinical nephrology; Bartters and Gitelmans syndromes of inherited hypokalemic alkalosis. Mutations in four different genes have been identified, each of which causes hypokalemic alkalosis, salt wasting and hypotension. These genetic studies have greatly advanced our understanding of renal physiology.

Ion transporter mutations in Gitelman's and Bartter's syndromes.

The application of modern techniques in molecular genetics to classic diseases in clinical nephrology is highlighted by the recent description of the molecular basis of Barriers and Gitelmans syndromes, A series of detailed studies are described that have resulted in the identification of specific mutations in four different genes, each of which causes hypokalemic alkalosis, salt wasting and hypotension. The importance of these genetic studies in understanding renal physiology and the regulation of blood pressure, and in developing new therapeutic strategies is discussed.

Bartter syndrome and focal segmental glomerulosclerosis: a possible link between two diseases

Abstract We describe a patient with signs and symptoms of classic Bartter syndrome. The patient tested negative for all known genetic abnormalities associated with this tubular disorder. Proteinuria was found within 1 year after the diagnosis of Bartter syndrome. A renal biopsy performed 6 months later, when her kidney function was normal, revealed focal segmental glomerulosclerosis (FSGS). We propose a link between stimulation of the renin-angiotensin system and sclerotic changes in the glomerulus. This lesion may explain previous reports of kidney failure in patients with Bartter syndrome.

Conversion from epoetin alfa to darbepoetin alfa for management of anaemia in a community chronic kidney disease centre: a retrospective cohort study.

BACKGROUND The management of anaemia in chronic kidney disease (CKD) to achieve current guideline goals is difficult and is hindered by multiple factors, including problems with the scheduling and adjustment of dosing of erythropoiesis-stimulating agents (ESAs) and the frequency of required ESA administration to achieve target haemoglobin (Hgb) levels. OBJECTIVE The primary objective of this study was to examine whether converting a large cohort of CKD patients receiving epoetin alfa to darbepoetin alfa would decrease the frequency of drug administration while permitting an acceptable management of CKD-related anaemia. METHODS In this retrospective cohort study of practice in a community-based CKD anaemia clinic, we evaluated the effects of conversion of a baseline group of 283 patients from epoetin alfa to darbepoetin alfa with a goal of decreasing the frequency of ESA administration while maintaining Hgb levels within a target range. The study observation period extended for 15 months after the initial conversion. An additional 256 CKD patients were started on darbepoetin alfa during the observation period and the frequency of their injections and the range of their Hgb levels were also monitored. RESULTS Following the conversion to darbepoetin alfa, we were able to increase the number of patients on once-monthly injections from 21% to 76% while keeping Hgb levels in the target range and maintaining stable blood pressure control. The mean number of ESA injections/patient/month decreased from 2.1 to 1.3. CONCLUSION In a community-based CKD anaemia clinic, conversion from epoetin alfa to darbepoetin alfa resulted in a decreased frequency of injections needed to maintain Hgb levels within an accepted target range.