Erika S.W. Jones

The Association of the R563Q Genotype of the ENaC With Phenotypic Variation in Southern Africa.

BACKGROUND The epithelial sodium channel (ENaC) may be a common underlying pathway for the development of primary hypertension. In South Africa, the R563Q variant of the ENaC is associated with low-renin-low-aldosterone hypertension and preeclampsia in black Africans and mixed-ancestry peoples. The purpose of this study was to investigate the prevalence of the R563Q variant in the multiethnic populations of South Africa, its association with hypertension and response to amiloride in patients with resistant hypertension. METHODS Samples were obtained from hypertensives and normotensive controls in Cape Town and Johannesburg, and unselected San living in the rural areas of the Northern Cape and Namibia. Resistant hypertensives with the R563Q variant were treated with amiloride. RESULTS One thousand nine hundred and thirty nine (1,468 hypertensives, 471 controls) subjects were recruited. Eighty-seven (5.9%) of the hypertensives were R563Q heterozygote vs. 8 (1.7%) of the normotensives (P < 0.0005). In the Namibian and Northern Cape San 19.5% and 18.8% of subjects were R563Q positive. There was no association with hypertension. Spot sodium excretion was lower in the San compared to urban subjects (7.3 vs. 12.2 mmol/mmol, P = 0.016). Twenty-two R563Q heterozygote patients with resistant hypertension received amiloride with a mean reduction in blood pressure (BP) of 36/17 mm Hg (P < 0.0001). CONCLUSIONS The R563Q variant is strongly associated with hypertension in urban areas in South Africa. The San are the likely origin of the variant, but it is not associated with hypertension, presumably due to their lower sodium intake. Screening patients with resistant hypertension in South Africa for the R563Q variant provides a feasible pharmacogenetic approach to treatment.

Outcome of patients with membranous lupus nephritis in Cape Town South Africa

BACKGROUND The kidney is one of the major target organs affected by systemic lupus erythematosus. Although proliferative forms of lupus nephritis (LN) occur more frequently than membranous LN (MLN), the latter appears to have a more favourable outcome. Only a few studies have reported the outcome of patients with MLN. METHODS A retrospective analysis of patients with biopsy-confirmed MLN from a single centre in South Africa treated from 1st January 2000 to 31st December 2009. RESULTS The mean age of the patients (n = 42) at onset of LN was 35.0 ± 12.8 years with 73.8% of the patients being of mixed ancestry (coloureds). Eleven patients (26.2%) reached the composite end point of death or end-stage renal disease or persistent doubling of serum creatinine. The overall median survival and median renal survival times were 82.3 ± 15.5 months (95% confidence interval 52.0-112.6) and 84.5 ± 15.0 months (55.1-113.8), respectively. Also, 5-year event-free survival and renal survival were 64 and 71%, respectively. On multivariate analysis, systolic blood pressure (BP) during follow-up (P = 0.029), diastolic BP during follow-up (P = 0.020) and attainment of complete remission at 6 months (P = 0.033) were factors associated with the composite end points. Although treatment with chloroquine was not significantly associated with the composite end points (P = 0.05), we found that patients who received chloroquine had better renal survival compared with those who did not (P = 0.007). CONCLUSIONS The outcome of patients with MLN in Cape Town is poorer than for similar patients reported from other centres across the world. Better BP control may significantly influence outcome of disease in these patients.

High Frequency of Variants of Candidate Genes in Black Africans with Low Renin-Resistant Hypertension.

OBJECTIVES Black subjects tend to retain salt and water, be more sensitive to aldosterone, and have suppression of plasma renin activity. Variants of the renal sodium channel (ENaC, SCNN1B) account for approximately 6% of resistant hypertension (RHT) in Blacks; other candidate genes may be important. METHODS Six candidate genes associated with low renin-resistant hypertension were sequenced in Black Africans from clinics in Kenya and South Africa. CYP11B2 was sequenced if the aldosterone level was high (primary aldosteronism phenotype); SCNN1B, NEDD4L, GRK4, UMOD, and NPPA genes were sequenced if the aldosterone level was low (Liddle phenotype). RESULTS There were 14 nonsynonymous variants (NSVs) of CYP11B2: 3 previously described and associated with alterations in aldosterone synthase production (R87G, V386A, and G435S). Out of 14, 9 variants were found in all 9 patients sequenced. There were 4 NSV of GRK4 (R65L, A116T, A142V, V486A): at least one was found in all 9 patients; 3 were previously described and associated with hypertension. There were 3 NSV of SCNN1B (R206Q, G442V, and R563Q); 2 previously described and 1 associated with hypertension. NPPA was found to have 1 NSV (V32M), not previously described and NEDD4L did not have any variants. UMOD had 3 NSV: D25G, L180V, and T585I. CONCLUSIONS A phenotypic approach to investigating the genetic architecture of RHT uncovered a surprisingly high yield of variants in candidate genes. These preliminary findings suggest that this novel approach may assist in understanding the genetic architecture of RHT in Blacks and explain their two fold risk of stroke.

Physiological Phenotyping for Personalized Therapy of Uncontrolled Hypertension in Africa

OBJECTIVES African and African American hypertensives tend to retain salt and water, with lower levels of plasma renin and more resistant hypertension. We tested the hypothesis that physiological phenotyping with plasma renin and aldosterone would improve blood pressure control in uncontrolled hypertensives in Africa. METHODS Patients at hypertension clinics in Nigeria, Kenya, and South Africa with a systolic blood pressure >140 mm Hg or diastolic pressure > 90 mm Hg despite treatment were allocated to usual care (UC) vs. physiologically individualized care (PhysRx). Plasma renin activity and aldosterone were measured using ELISA kits. Patients were followed for 1 year; the primary outcome was the percentage of patients achieving blood pressure <140 mm Hg and diastolic <90 mm Hg. RESULTS Results are presented for the 94/105 participants who completed the study (42 UC, 52 PhysRx). Control of both systolic and diastolic pressures was obtained in 11.1% of UC vs. 50.0% of PhysRx (P = 0.0001). Systolic control was achieved in 13.9% of UC vs. 60.3% of PhysRx (P = 0.0001); diastolic control in 36.1% of UC vs. 67.2% of PhysRx, vs. (P = 0.003). Number of visits and total number of medications were not significantly different between treatment groups, but there were differences across the sites. There were important differences in prescription of amiloride as specified in the PhysRx algorithm. CONCLUSIONS Physiologically individualized therapy based on renin/aldosterone phenotyping significantly improved blood pressure control in a sample of African patients with uncontrolled hypertension. This approach should be tested in African American and other patients with resistant hypertension. Registered as ISRCTN69440037.

Hypertension, end-stage renal disease and mesangiocapillary glomerulonephritis in methamphetamine users.

BACKGROUND Methamphetamine abuse has risen dramatically in South Africa. The chronic effects of abuse on the kidneys and blood pressure have not been documented. This study reviewed patients referred for evaluation of kidney disease and/or hypertension, who had been abusing methamphetamines. METHODS The records of patients referred to the renal unit between 2005 and 2013 who had been using methamphetamines were retrospectively reviewed. Patient demographics, biophysical parameters, blood pressure, renal function, renal ultrasound and biopsy findings, complications of chronic kidney disease and comorbidities were recorded. RESULTS Forty-seven patients were included in the study. Their mean age was 29 years. Hypertension was present in 42 (89.4%) of patients, with malignant hypertension in 21 (44.7%). Forty-five (95.7%) had chronic kidney disease (CKD), and 26 (55.3%) had end-stage renal disease. Renal biopsies were performed in 24 patients. Twelve (50.0%) of the biopsies showed hypertensive changes and 14 (58.3%) mesangiocapillary glomerulonephritis type 1, with deposition of IgM and C3 complement. CONCLUSION Methamphetamine use is associated with severe hypertension, mesangiocapillary glomerulonephritis and CKD.

Liddle’s syndrome in an African male due to a novel frameshift mutation in the beta-subunit of the epithelial sodium channel gene

Summary Resistant hypertension is a common clinical problem in South Africa and is frequently associated with low renin and aldosterone levels, especially in black Africans. In South Africa, novel variants in the epithelial sodium channel (ENaC) have been described to be associated with varying degrees of hypokalaemia and hypertension due to primary sodium retention. We report here a case of Liddle’s syndrome due to a novel c.1709del11 (p.Ser570Tyrfs*20) deletion in the beta-subunit of the ENaC in a young black African male. We discuss the likely pathogenesis of hypertension in this setting as well as the treatment options available in South Africa aimed at the ENaC. This case highlights the need for vigilance in detecting and appropriately treating low-renin and low-aldosterone hypertension in view of the frequency of the described variants of the ENaC channel in our cuntry. Specific therapy such as amiloride should be made more widely available.

Rationale and design of the comparison of three combination therapies in lowering blood pressure in Black Africans (CREOLE study): 2 X 3 factorial randomized single-blind multicentre trial

Background Current hypertension guidelines recommend the use of combination therapy as first‐line treatment or early in the management of hypertensive patients. Although there are many possible combinations of blood pressure(BP)–lowering therapies, the best combination for the black population is still a subject of debate because no large randomized controlled trials have been conducted in this group to compare the efficacy of different combination therapies to address this issue. Methods The comparison of 3 combination therapies in lowering BP in the black Africans (CREOLE) study is a randomized single‐blind trial that will compare the efficacy of amlodipine plus hydrochlorothiazide versus amlodipine plus perindopril and versus perindopril plus hydrochlorothiazide in blacks residing in sub‐Saharan Africa (SSA). Seven hundred two patients aged 30‐79 years with a sitting systolic BP of 140 mm Hg and above, and less than 160 mm Hg on antihypertensive monotherapy, or sitting systolic BP of 150 mm Hg and above, and less than 180 mm Hg on no treatment, will be centrally randomized into any of the 3 arms (234 into each arm). The CREOLE study is taking place in 10 sites in SSA, and the primary outcome measure is change in ambulatory systolic BP from baseline to 6 months. The first patient was randomized in June 2017, and the trial will be concluded by 2019. Conclusions The CREOLE trial will provide unique information as to the most efficacious 2‐drug combination in blacks residing in SSA and thereby inform the development of clinical guidelines for the treatment of hypertension in this subregion.

Disparities in dialysis allocation: An audit from the new South Africa

End Stage Kidney Disease (ESKD) is a public health problem with an enormous economic burden. In resource limited settings management of ESKD is often rationed. Racial and socio-economic inequalities in selecting candidates have been previously documented in South Africa. New guidelines for dialysis developed in the Western Cape have focused on prioritizing treatment. With this in mind we aimed at exploring whether the new guidelines would improve inequalities previously documented. A retrospective study of patients presented to the selection committee was conducted at Groote Schuur Hospital. A total of 564 ESKD patients presented between 1 January 2008 and 31 December 2012 were assessed. Half of the patients came from low socioeconomic areas, and presentation was late with either overt uremia (n = 181, 44·4%) or fluid overload (n = 179, 43·9%). More than half (53·9%) of the patients were not selected for the program. Predictors of non-acceptance onto the program included age above 50 years (OR 0·3, p = 0·001), unemployment (OR 0·3, p<0·001), substance abuse (OR 0·2, p<0·001), diabetes (OR 0·4, p = 0·016) and a poor psychosocial assessment (OR 0·13, p<0·001). Race, gender and marital status were not predictors. The use of new guidelines has not led to an increase in inequalities. In view of the advanced nature of presentation greater efforts need to be made to prevent early kidney disease, to allocate more resources to renal replacement therapy in view of the loss of young and potentially productive life.

MPS 14-09 PHYSIOLOGICALLY INDIVIDUALISED THERAPY FOR RESISTANT HYPERTENSION IN AFRICA: PRELIMINARY REPORT

Objective: To determine whether individualized therapy for resistant hypertension based on physiological determinants of salt and water retention will achieve better control of blood pressure, compared to guideline-based care, among black Africans. Design and Method: Patients with resistant hypertension who attend Hypertension clinics in three African medical centres were randomized to usual care versus physiologically individualized therapy. Data were gathered on patients at randomization, one, six and twelve months. Data were collected on plasma renin and aldosterone levels, blood pressure, medications, investigations, visits, adverse drug effects and outcome events. Local ethics committees approved the study and patients gave signed informed consent. Patients were randomized to usual care versus therapy according to renin and aldosterone: aldosterone antagonist for low renin/high aldosterone; amiloride for low renin/low aldosterone; ARB for high renin/high aldosterone. Other medications were added according to blood pressure response. The primary outcome was the proportion of patients achieving target blood pressure at one year on the two strategies. Secondary outcomes were the number of visits, number of medications, adverse effects of medications and adverse outcomes such as decline in GFR, hypokalemia, hyperkalemia, and admission to hospital with cardiovascular outcomes such as stroke and heart failure. Data were analysed with SPSS. Results: One hundred and two patients were enrolled. There were no differences in baseline characteristics between the patients that received standard guideline based care and those that received individualised care. BP targets (< 140/90 mmHg) were reached in 25% for SBP and 43% for DBP in the standard care arm and 75% and 65% in the physiological care arm at one year, p < 001 for SBP and P = 0.024 for DBP. The BP drop was 19 ± 25/5 ± 18 in the standard care arm and 29 ± 25/5 ± 16 in the physiological care arm (NS). Conclusions: Individualised therapy for hypertension increased the proportion of patients reaching target blood pressures at one year in these preliminary data.